Merkel Cell Carcinoma: Clinical Guidelines

List of Abbreviations

SLNB – sentinel lymph node biopsy (listed in the NMU as Lymph node biopsy)

WHO – World Health Organization

PTP – primary tumor identified

IV – intravenous

CI – confidence interval

MCC – Merkel cell carcinoma

CT – computed tomography

LAE – lymphadenectomy

RT – radiotherapy

LNs – lymph nodes

PT – physical therapy

mAb – monoclonal antibodies (ATC code: L01XC)

ICD-10 – International Classification of Diseases 10th Revision

MRI – magnetic resonance imaging

PET – positron emission tomography

AIDS – acquired immunodeficiency syndrome

US – ultrasound examination

AJCC – American Joint Committee on Cancer

AUC – area under the plasma concentration-time curve (mg/mL × min)

MCPyV – Merkel cell polyomavirus

UICC – Union for International Cancer Control

** – vital and essential drugs

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages specified in the drug's package insert)

Terms and Definitions

• Adjuvant chemotherapy – chemotherapy administered after local tumor treatment to eradicate or long-term suppress micrometastases.

• Sentinel lymph node biopsy – a method of obtaining histological material from a lymph node considered to be the first in the path of lymphogenous tumor spread. The presence or absence of metastases determines the indications for complete lymphadenectomy.

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

• Immunohistochemical examination – a microscopic tissue examination method that provides the most specific identification of target substances and is based on treating sections with labeled specific antibodies against the target substance (antigen).

• Incisional punch biopsy – a method of obtaining a full-thickness skin tissue sample, where the lateral resection margins may contain tumor (or nevus) elements. Performed using a special punch instrument (1 to 5 mm in diameter). Used in exceptional cases when excisional biopsy is not feasible.

• Locally advanced unresectable disease – tumor spread is limited to a single area, but radical surgery is impossible due to extensive involvement.

• PD1 – programmed cell death protein 1.

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

• Systemic chemotherapy – the administration of drugs orally, subcutaneously, intravenously, or intramuscularly, designed for a general antitumor effect.

• Transit metastases – metastases located between the primary tumor and the regional collector or distal to the primary tumor.

• ECOG (Eastern Cooperative Oncology Group) – a 5-point scale for assessing the overall performance status of a cancer patient before, during, and after treatment (recommended by the Eastern Cooperative Oncology Group).

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

• 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 during the early and late rehabilitation periods, as well as the period of residual disease symptoms, provided in rehabilitation, physiotherapy, exercise therapy, reflexology, manual therapy, psychotherapy, medical psychology, and speech therapy (defectology) departments (rooms) providing outpatient medical care, in day care settings, and by mobile home-visit teams (including sanatorium-resort organizations).

• Excisional biopsy of a skin neoplasm – a method of obtaining a skin tissue sample by entirely (completely) removing the neoplasm with a small (1–3 mm) margin of surrounding healthy tissue. This method of obtaining morphological material is preferred when cutaneous melanoma is suspected.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Merkel cell carcinoma (MCC) – a rare primary malignant skin tumor with epithelial and neuroendocrine differentiation (according to the World Health Organization (WHO) classification) [1].

Rare localizations of MCC have also been described: mucous membranes of the head and neck, and genitalia [173, 174, 175]

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

Several known risk factors for this disease exist:

• age over 65 years. The median age of the majority (71.6%) of patients at diagnosis is 69–70 years, with a 5-10-fold increase in incidence among patients over 70 compared to those under 60;

• ultraviolet radiation exposure;

• immunosuppressive state of the organism. A 2–3-fold increase in the risk of MCC has been noted in patients suffering from acquired immunodeficiency syndrome (AIDS);

• ~5-fold increase among organ transplant recipients;

• 15.7-fold increase in the risk of MCC in patients with B-cell neoplasms [2–6].

In January 2008, H. Feng et al. presented evidence of potential viral oncogenesis. A polyomavirus, named Merkel cell polyomavirus (MCPyV), was identified for the first time. Its sequences were detected in 8 (80%) of 10 MCC samples, but only in 5 (8%) of 59 control samples from various body sites and in 4 (16%) of 25 skin control samples. The authors reported that in 6 of 8 MCPyV-positive MCC samples, viral DNA was found integrated into the tumor genome. Thus, the authors concluded that MCPyV may be a contributing factor to MCC development [7–9]. Studies on MCC and MCPyV, as well as other risk factors, have significantly expanded our knowledge of MCC pathogenesis, but the cell of origin remains unknown. Merkel cells, or neuroendocrine cells of the skin, are thought to be the potential source of MCC due to their phenotypic similarity. However, for several reasons, such as the heterogeneous differentiation of MCC and the postmitotic nature of Merkel cells, it is unlikely that MCC develops from differentiated Merkel cells. Epidermal-derived skin stem cells are likely the cells from which MCC develops. The question of the cell of origin for MCC still needs to be resolved in future studies [11].

1.3 Epidemiology of the Disease or Condition

Merkel cell carcinoma is not classified as a separate nosological entity in Russia; incidence and mortality rates are recorded under C44 overall (other malignant neoplasms of skin). While approximately 1,500 new cases of MCC are registered annually in the USA and ~2,500 in the European Union countries [12–15], considering the population sizes of the USA, the EU, and Russia, one can estimate roughly 650 new cases of MCC per year.

1.4 Features of Coding the Disease or Condition

C44 Other malignant neoplasms of skin

C44.0 Skin of lip

C44.1 Skin of eyelid, including canthus

C44.2 Skin of ear and external auricular canal

C44.3 Skin of other and unspecified parts of face

C44.4 Skin of scalp and neck

C44.5 Skin of trunk

C44.6 Skin of upper limb, including shoulder area

C44.7 Skin of lower limb, including hip region

C44.8 Skin overlapping lesions of skin

C44.9 Malignant neoplasm of skin, unspecified

1.5 Classification of the disease or condition

International Histological Classification (WHO Classification, 4th Edition, 2018)

8247/3 Merkel cell carcinoma

TNM Staging of Merkel Cell Carcinoma

Staging of Merkel cell carcinoma according to the American Joint Committee on Cancer (AJCC) / Union for International Cancer Control (UICC) TNM classification, 8th edition (2017) [16]. Pathological examination of biopsy (surgical) material for morphological verification of the diagnosis is mandatory for staging Merkel cell carcinoma. Lymph node assessment to establish the stage is performed using clinical examination, instrumental studies, and sentinel lymph node biopsy. A unified classification is used for MCC [16, 17, 18].

The T category reflects the extent of the primary tumor and includes the following gradations.

Primary tumor (pT)

UICC TNM 8 pT is identical to T.

pTX Primary tumor cannot be assessed

p0 No evidence of primary tumor (lymph node metastases/distant metastases without identification of primary tumor (PTP))

pTis In situ primary tumor

pT1 ≤2 cm in greatest dimension

pT2 >2 cm, but ≤5 cm in greatest dimension

pT3 >5 cm in greatest dimension

pT4 Primary tumor invades deep structures, such as muscle, bone, or cartilage

NB. Measurement by morphological examination is possible if clinical examination/evaluation data are lacking

Regional lymph nodes (N) - the N category indicates the presence or absence of metastases in regional lymph nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastases

N1 Metastases in regional LNs

N2 In-transit metastases without regional LN metastasis

N3 In-transit metastases with regional LN metastasis

Regional lymph nodes (pN) – pathologic/morphological stage

pNX Regional LNs cannot be assessed

pN0 No regional LN metastasis on histological examination

pN1 Regional LN metastasis on histological examination

pN1a(sn) Micrometastases detected by sentinel lymph node biopsy (SLNB)

pN1a Micrometastases detected by lymphadenectomy (LAD)

pN1b Macrometastases in LNs (clinically detected)

pN2 In-transit metastases without regional LN metastasis*

pN3 In-transit metastases with regional LN metastasis*

*Metastases located (1) between the primary tumor and the regional basin or (2) distal to the primary tumor.

For tumors located predominantly on one side of the body (left or right), the regional lymph nodes are considered to be:

• head and neck: ipsilateral parotid, submandibular, cervical, and supraclavicular lymph nodes;

• chest wall: ipsilateral axillary lymph nodes;

• upper extremity: ipsilateral epitrochlear and axillary lymph nodes;

• abdomen, lower back, and buttocks: ipsilateral inguinal lymph nodes;

• lower extremity: ipsilateral popliteal and inguinal lymph nodes;

• anal verge and perianal skin: ipsilateral inguinal lymph nodes.

If a tumor is located in watershed areas, lymph nodes on both sides may be considered regional.

If metastases are detected in lymph nodes outside the specified regional metastatic zones, they should be classified as distant metastases.

The M criterion characterizes the presence or absence of distant metastases

M0 No distant metastases

M1 Presence of distant metastases

M1a Presence of distant metastases to the skin, subcutaneous tissue, and distant LNs

M1b Presence of distant metastases to the lungs

M1c Presence of distant metastases to other visceral organs

The TNM staging groups for Merkel cell carcinoma are presented in Table 1 (clinical) and Table 2 (pathological).

Table 1. TNM staging groups for MCC, clinical

Table 2. TNM staging groups for Merkel cell carcinoma, pathological

Merkel cell carcinoma metastases without an identified primary site in peripheral lymph nodes of a single region should be staged as stage IIIA (Table 2).

Comment: differences between the updated 8th edition staging system and the previous version.

1. For the new staging system, it is important to specify how the disease stage was determined: clinically or pathologically/morphologically. This is important regarding the risk of disease recurrence and patient survival. For example, if LNs are determined as clinically negative only (i.e., the physician cannot perform an SLNB for the patient or refer them to a center where this can be done), this is less accurate than pathologically/morphologically negative LNs, because LN micrometastases in MCC are detected in one-third of patients with clinically negative LNs. Since morphological diagnosis and negative morphological LN status via SLNB are more accurate, patients whose LNs are staged this way have a lower chance of recurrence/progression compared to clinically negative patients, because one-third of the latter actually already have early LN involvement that we cannot detect clinically.

2. Patients presenting initially with LN metastases without a primary tumor (PUP) are now staged separately from patients with LN metastases and a known primary tumor. Numerous studies have shown that patients with LN metastases without a PUP have better survival rates compared to patients with a known primary tumor [19–21]. For this reason, these 2 substages of stage III disease are separated.

1.6 Clinical presentation of the disease or condition

The clinical presentation is non-specific, and suspecting MCC prior to morphological verification is extremely difficult. Typically, the patient reports the appearance of a painless, solitary, uniform, non-ulcerated pink or red-purple skin lesion (sometimes without skin discoloration) that grows rapidly (doubling in size or more over the past 3 months) [22]. Lesions are most frequently located on sun-exposed areas of the skin (head, neck, extremities), and the skin may often appear unchanged. Ulceration of the tumor lesion as well as multifocal disease spread may occasionally be observed. In 50% of cases, MCC is located in the head and neck region, in 40% on the skin of the extremities, and in 10% on the skin of the trunk and genitalia [23]. Cases of localization on the vaginal mucosa, etc., have also been reported [24].

Thus, an important clinical sign should be emphasized—rapid growth of a painless skin neoplasm without characteristic dermoscopic features (which would classify it as a benign neoplasm or other malignant skin tumor). Such a neoplasm should raise suspicion of a malignant neoplasm among primary care physicians (general practitioners, internists, surgeons, or dermatologists) and prompt morphological (histological or, less preferably, cytological) verification.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

1) anamnesis data (appearance of a painless skin lesion and its rapid growth);

2) physical examination findings and a thorough examination of the skin and peripheral LNs (typically a single pink or red-purple skin nodule with a firm-elastic consistency without surface ulceration; advanced forms may present with multifocal spread and ulceration of the skin nodule surface);

3) pathomorphological examination data of skin biopsy (surgical) material using immunohistochemical methods (with standard hematoxylin and eosin staining, the pathologist suspects a diagnosis of MCC, which is subsequently confirmed by immunohistochemical phenotyping using antibodies against cytokeratin 20).

Table 3 outlines the examination plan based on the results of the skin lesion biopsy and clinical examination. Recommendations for the medical interventions themselves are presented in the respective sections.

2.1 Complaints and Anamnesis

2.2 Physical Examination

Comment: during the examination, attention should be paid to the size of the skin lesion, changes in the color and surface of the skin overlying the lesion, the presence/absence of infiltration of surrounding tissues, the mobility of the lesion relative to underlying tissues, and the size and consistency of regional LNs. Assessing the presence/absence of multiple primary tumors as well as other malignant skin neoplasms is also important. Patients with MCC are more frequently diagnosed with other malignancies than others (in about 55% of cases), most commonly other skin tumors: cutaneous squamous cell carcinoma, basal cell carcinoma, melanoma, and other precancerous skin conditions (actinic keratosis).

2.3 Laboratory Diagnostics

Comment: if necessary for differential diagnosis with other malignant tumors, immunohistochemical determination of the expression of thyroid transcription factor 1 in the tumor, neuroendocrine differentiation markers—chromogranin A, synaptophysin, CD56, and the cell proliferation marker Ki-67 [1, 57-67, 25, 159, 160] [58, 66, 67, 158].

2.4 Instrumental Diagnostics

Table 3. Examination plan depending on the results of skin lesion biopsy and clinical examination

Comment: treatment planning should not be formulated until data on the extent of the tumor process are obtained. PET-CT is the standard staging diagnostic method for MCC in most developed countries. The use of positron emission tomography (PET)/CT to assess the extent of the tumor process alters the stage in 22% of cases. A meta-analysis of 6 studies demonstrated 90% sensitivity and 98% specificity of the method. In practice, this study can be partially replaced by contrast-enhanced CT of the chest, abdomen, and pelvis with i.v. contrast.

If the optimal scope of diagnostic imaging cannot be performed within 4 weeks after establishing the diagnosis, chest CT may be replaced by chest radiography, and contrast-enhanced CT of the abdomen and pelvis with i.v. contrast may be replaced by ultrasound of the abdominal and pelvic organs [26, 27, 44, 45, 47–49].

Comment: if it is impossible to perform contrast-enhanced brain MRI (waiting time for the study exceeds 1 month), contrast-enhanced brain CT is acceptable. Brain CT without i.v. contrast is not recommended.

Comment: in localized forms of MCC, whole-body bone scintigraphy is performed in the presence of bone pain or elevated alkaline phosphatase levels.

[1]Taking into account histological report data and clinical examination.

[2]Performed in specialized centers. The procedure must be completed no later than 3 months after establishing the diagnosis. For stage 0 – not required.

2.5 Other Procedures

Comment: excisional biopsy is the recommended standard for diagnosing cutaneous melanoma. Given that MCC lacks a specific clinical or dermoscopic picture, it is consensually recommended to use the same approach as for cutaneous melanoma. However, in a number of clinical situations (e.g., large lesion area, etc.), excisional biopsy of the entire lesion is associated with significant difficulties and unjustified surgical trauma for the patient. In this case, it is safe to perform an incisional (or punch) biopsy through the full thickness of the skin. According to a systematic review of 9 studies, including randomized controlled trials, performing an incisional biopsy of melanoma does not adversely affect prognosis [36]. Similar data for MCC are not available.

Comments: Given the orphan status of the disease, clinical trials for Merkel cell carcinoma are lacking; these recommendations are based on general principles and approaches for non-melanoma skin cancers and melanoma.

For primary tumors, it is mandatory to indicate the size of the primary focus and its extension to the underlying muscle, fascia, bone, or cartilage.

When formulating the conclusion based on the results of the pathomorphological examination of the surgical specimen (MCC metastases in regional lymph nodes):

1) number of removed lymph nodes;

2) number of affected lymph nodes;

3) nature of lymph node involvement:

>– partial involvement (number of lymph nodes);

>– total involvement (number of lymph nodes);

>– capsular breakthrough (number of lymph nodes).

Cytological examination of skin smear-imprints. Analysis of the cytological material from the N.N. Blokhin National Medical Research Center of Oncology showed that the tumor has a characteristic cytological picture. Therefore, the use of the cytological method appears advisable. As a rule, fine-needle aspiration biopsy of both the primary tumor and metastatic foci is performed, followed by cytological examination. The smears are air-dried, then fixed in Leishman stain, and counterstained with an azure-eosin mixture. Primarily, at low microscope magnification, this is a very dense cellular infiltrate, predominantly composed of round undifferentiated cells arranged in a solid pattern; glandular-like structures may also be encountered in certain areas. As a rule, even at low magnification, a large number of mitoses is noted. At high microscope magnification, the distinguishing features of the tumor are clearly pronounced signs of cellular malignancy, signs of neuroendocrine differentiation (resembling small cell lung cancer), the presence of characteristic perinuclear globules, and a large number of mitoses. The spectrum of morphological diversity of MCC varies from a dense cellular infiltrate to sparsely distributed cells and dense clusters of disrupted pyknotic nuclei. In a typical MCC presentation, the cytoplasm is either absent or identified as a narrow rim, although variants with more abundant cytoplasm occur, where the epithelial nature of the cells is more clearly revealed [25]. Other hematological stains can also be used in clinical practice. If necessary, an immunocytochemical method using a panel of antibodies for neuroendocrine tumors can be employed [56].

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

3.1. Treatment of localized disease stages (I-II)

Comment: adjuvant radiation therapy (RT) is additionally administered according to indications [27, 78, 79]. The resection margin from the visible edge of the tumor (at least 1 cm and no more than 2 cm) should be determined based on clinical feasibility. Margins from the visible edges of the tumor (or the scar after a prior excisional biopsy) are not recommended to be extended by more than 2 cm, as this will lead to unnecessary manipulations associated with the closure of the postoperative wound (e.g., various types of complex plastic surgery). At the same time, postoperative RT to the primary tumor area, initiated immediately after the healing of the postoperative wound, can significantly improve the prognosis [24, 27, 75–82].

Comment: Surgical treatment must be performed within 15 days from the moment of morphological verification (in the presence of indications for surgical treatment and the absence of contraindications).

Table 5. Recommended RT doses in patients with stage II MCC [27]

Comment: the timing of initiation of adjuvant RT should be within 4–6 weeks, but no later than 8 weeks from the moment of surgical treatment (in case of complete healing of the postoperative scar). The presence of a lymphocele is not a reason to delay the start of RT (regular lymph evacuation by surgeons is possible). Whenever possible, one should strive for an earlier start of adjuvant RT after surgical treatment [27].

3.2. Treatment of patients with resectable stage III disease

Comment: patients with stage III MCC undergoing LND are recommended to have the most complete removal possible of the subcutaneous adipose tissue of the anatomical region in which MCC metastases are detected (e.g., levels Ib–V of the neck fat (Ia – by indications), levels I–III of the axillary fat, superficial and deep inguinal lymph nodes). In case of clinically detected involvement of deep inguinal lymph nodes, great attention should be paid to the external iliac lymph nodes. Some researchers, in the case of massive involvement of deep inguinal lymph nodes (more than 3) or involvement of Cloquet's (Rosenmüller's) node–node, recommend expanding the scope of surgery to include the removal of ipsilateral external iliac lymph nodes.

Comment: an increase in survival has not been demonstrated in any of the available retrospective studies. However, individually for stage III disease, the administration of adjuvant chemotherapy according to the EC or EP regimen may be considered (in the absence of contraindications) in cases of young patient age and negative morphological factors: involvement of more than 4 lymph nodes, extension of tumor cells beyond the lymph node capsule.

Table 6. Recommended RT doses in patients with stage III MCC [27]

¹LND is recommended in the presence of clinically altered axillary or inguinal lymph nodes, followed by RT as indicated.

²Technique of step-down reduction of radiation field sizes.

³RT after surgical treatment is indicated in cases of multiple lymph node metastases or extracapsular lymph node extension.

Comment: adjuvant RT should be initiated within 8 weeks after surgery, provided there are no postoperative complications. Whenever possible, an earlier start of adjuvant RT following surgery should be pursued [27].

3.3. Treatment of patients with metastatic and unresectable Merkel cell carcinoma (stage III unresectable – IV)

Comments: The recommended timeframe for initiating medical therapy is within 15 days from the diagnosis of metastatic and/or unresectable MCC, barring any treatment contraindications or limitations due to comorbidities.

Table 7. Immunotherapy regimens used for the treatment of metastatic and unresectable MCC in the 1st (or subsequent) line of therapy

Table 8. Chemotherapy regimens used in the treatment of metastatic and unresectable MC [164]

Comment: Given the orphan disease status, large randomized clinical trials for chemotherapy are unavailable; historically, regimens recommended for small cell lung cancer treatment have been used due to phenotypic similarity [98,165]. The chemotherapy standard for CM is the combination of etoposide** with cisplatin** or carboplatin** (EP/EC regimens). Carboplatin** is used in debilitated patients and in renal impairment. Typically, 6 cycles of first-line CT are administered. Every 2–3 courses, control examination is performed to assess treatment efficacy. If disease progression develops within 6 months after completion of first-line CT, second-line CT is administered according to the specified regimens. If disease progression develops after 6 months or longer, it is possible to return to the CT regimen used in the first line (EC/EP). As a rule, 4–6 cycles of second-line CT are administered. Treatment efficacy is assessed every 2 cycles of CT. With further disease progression, reserve regimen CT is administered (typically, monotherapy with topotecan or etoposide**).

If clinical trials are available at the institution, participation in a clinical trial is recommended.

PD-1 blocking monoclonal antibodies (#pembrolizumab** (ATC – L01XC18), #nivolumab** (ATC – L01XC17) and PD-L1 (avelumab** (ATC – L01XX31)) may be used.

Programmed cell death ligand 1 (PD-L1) is expressed on the surface of MC tumor cells as well as on cells of the tumor microenvironment, suggesting the potential for PD-1 and PD-L1 inhibitors in the treatment of this condition [99, 100], which has been confirmed by data from several clinical trials [101–104]. The objective response rate for anti-PD-1 and anti-PD-L1 antibodies ranged from 32% when used in second and subsequent lines to 71.4% when used in first-line therapy, with 6-month progression-free survival rates of 40% [103] and 67% [101], respectively, and an expected 1-year progression-free survival rate of 30% when used in second and subsequent lines of therapy. Based on these data, in 2017, an anti-PD-L1 antibody (avelumab**) was approved for the first time globally for the treatment of patients with metastatic and/or unresectable MC. Subsequently, #pembrolizumab** was approved. Treatment regimens are presented in Table 10 [99–107].

• When administering systemic antineoplastic therapy, when calculating drug doses based on body surface area or body weight, it is recommended to round the actual doses within 5% of the calculated doses [139, 140].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence – 5).

3.4. Pain Management

Principles of pain management and optimal selection of analgesic therapy in Merkel cell carcinoma patients with chronic pain syndrome comply with the pain management principles outlined in the clinical guidelines "Chronic Pain Syndrome in Adult Patients Requiring Palliative Medical Care".

3.5. Supportive care in patients with Merkel cell carcinoma

Principles of treatment and prevention of nausea and vomiting in patients with Merkel cell carcinoma comply with the principles outlined in the guidelines "PREVENTION AND TREATMENT OF NAUSEA AND VOMITING" (Authors: Vladimirova L.Yu., Gladkov O.A., Kogoniya L.M., Koroleva I.A., Semiglazova T.Yu. DOI: 10.18027 / 2224–5057–2018–8–3s2–502–511, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-35.pdf)

Principles of treatment and prevention of bone complications in patients with Merkel cell carcinoma comply with the principles outlined in the guidelines "USE OF OSTEOMODIFYING AGENTS FOR THE PREVENTION AND TREATMENT OF BONE PATHOLOGY IN MALIGNANT NEOPLASMS" (Authors: Manzyuk L.V., Bagrova S.G., Kopp M.V., Kutukova S.I., Semiglazova T.Yu. DOI: 10.18027 / 2224–5057–2018–8–3s2–512–520, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-36.pdf)

The principles of prevention and treatment of infectious complications and febrile neutropenia in patients with Merkel cell carcinoma correspond to the guidelines set out in the clinical recommendations "MANAGEMENT OF INFECTIOUS COMPLICATIONS OF FEBRILE NEUTROPENIA AND ADMINISTRATION OF COLONY-STIMULATING FACTORS" (Authors: Sakaeva D. D., Orlova R. V., Shabaeva M. M. DOI: 10.18 027 / 2224–5057–2018–8–3s2–521–530, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-37.pdf)

The principles of prevention and treatment of hepatotoxicity in patients with Merkel cell carcinoma correspond to the guidelines set out in the clinical recommendations "MANAGEMENT OF HEPATOTOXICITY" (Authors: Tkachenko P. E., Ivashkin V. T., Maevskaya M. V. DOI: 10.18 027 / 2224–5057–2018–8–3s2–531–544, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-38.pdf)

The principles of prevention and treatment of cardiovascular complications in patients with Merkel cell carcinoma correspond to the guidelines set out in the clinical recommendations "PRACTICAL GUIDELINES FOR THE MANAGEMENT OF CARDIOVASCULAR TOXICITY OF ANTICANCER DRUG THERAPY" (Authors: Vitsenya M. V., Ageev F. T., Gilyarov M. Yu., Ovchinnikov A. G., Orlova R. V., Poltavskaya M. G., Sycheva E. A. DOI: 10.18 027 / 2224–5057–2018–8–3s2–545–563, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-39.pdf)

The principles of prevention and treatment of skin complications in patients with Merkel cell carcinoma correspond to the guidelines set out in the clinical recommendations "PRACTICAL GUIDELINES FOR THE DRUG TREATMENT OF DERMATOLOGICAL REACTIONS IN PATIENTS RECEIVING ANTICANCER DRUG THERAPY" (Authors: Koroleva I. A., Bolotina L. V., Gladkov O. A., Gorbunova V. A., Kruglova L. S., Manzyuk L. V., Orlova R. V. DOI: 10.18 027 / 2224–5057–2018–8–3s2–564–574, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-40.pdf)

The principles of nutritional support in patients with Merkel cell carcinoma correspond to the guidelines set out in the clinical recommendations "PRACTICAL GUIDELINES FOR NUTRITIONAL SUPPORT IN CANCER PATIENTS" (Authors: Sytov A. V., Leyderman I. N., Lomidze S. V., Nekhaev I. V., Khoteev A. Zh. DOI: 10.18 027 / 2224–5057–2018–8–3s2–575–583, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-41.pdf

The principles of prevention and treatment of nephrotoxicity in patients with Merkel cell carcinoma correspond to the guidelines set out in the clinical recommendations "PRACTICAL GUIDELINES FOR THE MANAGEMENT OF ANTICANCER DRUG-INDUCED NEPHROTOXICITY" (Authors: Gromova E. G., Biryukova L. S., Dzhumabaeva B. T., Kurmukov I. A. DOI: 10.18 027 / 2224–5057–2018–8–3s2–591–603, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-44.pdf

The principles of prevention and treatment of thromboembolic complications in patients with Merkel cell carcinoma correspond to the guidelines set out in the clinical recommendations "PRACTICAL GUIDELINES FOR THE PREVENTION AND TREATMENT OF THROMBOEMBOLIC COMPLICATIONS IN CANCER PATIENTS" (Authors: Somonova O. V., Antukh E. A., Elizarova A. L., Matveeva I. I., Selchuk V. Yu., Cherkasov V. A., DOI: 10.18 027 / 2224–5057–2018–8–3s2–604–609, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-45.pdf)

The principles of prevention and treatment of the consequences of drug extravasation in patients with Merkel cell carcinoma correspond to the guidelines set out in the clinical recommendations "GUIDELINES FOR THE MANAGEMENT OF ANTICANCER DRUG EXTRAVASATION" (Author: Buydenok Yu. V. DOI: 10.18 027 / 2224–5057–2018–8–3s2–610–616, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-46.pdf)

The principles of prevention and treatment of immune-mediated adverse events in patients with Merkel cell carcinoma correspond to the guidelines set out in the clinical recommendations "PRACTICAL GUIDELINES FOR THE MANAGEMENT OF IMMUNE-MEDIATED ADVERSE EVENTS" (Authors: Protsenko S. A., Antimonik N. Yu., Bershtein L. M., Novik A. V., Nosov D. A., Petenko N. N., Semenova A. I., Chubenko V. A., Yudin D. I., DOI: 10.18 027 / 2224–5057–2018–8–3s2–636–665, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-48.pdf)

3.6. Dietary therapy

Dietary therapy is not used for the treatment of Merkel cell carcinoma.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Currently, clinical studies involving patients with Merkel cell carcinoma are lacking for most types of medical rehabilitation. These recommendations are based on the fact that numerous studies and systematic reviews [170] have proven that various types of medical rehabilitation significantly accelerate functional recovery, shorten hospital stays after surgery, and reduce the incidence of complications and mortality rates in patients with other malignant neoplasms.

The goals of rehabilitation should include: restoring the range of motion in the operated body part, restoring muscle tone, increasing muscle strength of the operated limb, correcting muscle imbalance, and restoring walking skills.

4.1. Pre-rehabilitation

Comment: It is important to advise the patient to increase physical activity 2 weeks before surgery in order to reduce the hospital stay and the risk of postoperative complications, as well as to improve the quality of life in the postoperative period [109].

4.2. Surgical treatment

4.2.1. First stage of rehabilitation

Comment: the exercise therapy program must be developed individually in each specific case, taking into account the characteristics and extent of the surgery.

4.2.2. Second stage of rehabilitation

4.2.3. Third stage of rehabilitation

4.3. Chemotherapy

4.4. Radiation therapy

4.5. Principles of psychological rehabilitation in patients with malignant skin neoplasms

Given that Merkel cell carcinoma is a rare skin tumor, the principles of psychological rehabilitation described below apply to patients with skin neoplasms in general, with the majority of studies referencing melanoma and other tumors.

Comment: Scientific research in psycho-oncology most frequently identifies 3 coping styles among melanoma patients:

(1) active behavioral coping with emotional, physical, and social difficulties associated with the disease and treatment;

(2) active cognitive coping, including attitudes, beliefs, and reflections about the disease;

(3) avoidance coping, involving attempts to actively avoid problems or indirectly reduce emotional stress through distraction.

Overall, studies show that patients who use active (problem-oriented) survival strategies demonstrate better adaptation to the disease than those who use passive or avoidant survival styles [148, 149, 150, 151]

Comment: The results of psychotherapeutic interventions demonstrate low levels of depression, confusion, asthenia, apathy, and overall depressed mood among melanoma patients [148]. Over 5 years of follow-up, these researchers were able to demonstrate that psychological and biological changes, in turn, correlated with relapse and survival rates [152]. A phase II study using a patient questionnaire prior to medical therapy was conducted for patients with chemotherapy-resistant metastatic Merkel cell carcinoma. It was shown that patients experienced anxiety and a sense of "shock" upon diagnosis (often delayed). However, no reports of impacts on cognitive function or daily life were received, though both patients and their relatives reported anxiety and fear regarding the unknown outcome of the disease [153].

5. Prevention and Dispensary Observation

To date, there is no consensus regarding the frequency and intensity of follow-up for patients with cutaneous melanoma. The goals of patient monitoring should be the early detection of disease recurrence and distant metastases, as well as the provision of psychosocial support.

Table 9. Scope of examination

Comment: the goal of monitoring is the earliest possible detection of disease progression for the prompt initiation of chemotherapy, radiation therapy, or surgical treatment, depending on the identified situation.

6. Organization of Medical Care

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

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

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

3) based on these clinical guidelines;

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

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

If an oncological disease is suspected or detected in a patient, general practitioners, district general practitioners, general family physicians, specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for a consultation at an outpatient cancer center, a primary oncology office, or a primary oncology 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.

If it is impossible to obtain biopsy (surgical) material or perform other diagnostic tests within the medical organization that incorporates the outpatient cancer center (primary oncology office, primary oncology department), the attending physician shall refer the patient to an oncological dispensary or a medical organization providing care to cancer patients.

The timeframe for performing pathomorphological examination of biopsy (surgical) material required for the morphological verification of a malignant neoplasm must not exceed 15 working days from the date the material is received by the pathomorphological bureau (department).

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

All histological specimens suspected of being cutaneous melanoma should preferably be reviewed at reference centers or National Medical Research Centers of Oncology. The recommendation to obtain a second opinion regarding a case suspected of cutaneous melanoma is based on expert opinion, which suggests that given the rarity of this pathology, pathologists in regional pathomorphological bureaus or departments of pathological anatomy, or laboratory diagnosticians in cytology departments, may lack sufficient diagnostic experience and fail to acquire it over their careers. Therefore, the use of telemedicine consultations (scans of histological or cytological specimens) or the direct transfer of the specimens themselves for consultation to reference centers possessing the required level of expertise (consultation of at least 10 cases per year) appears most appropriate.

The oncologist at the outpatient cancer center (primary oncology office, primary oncology department) shall refer the patient to an oncological dispensary or medical organizations providing care to cancer patients to clarify the diagnosis (if the oncologist at the outpatient cancer center, primary oncology office, or department is unable to establish the diagnosis, including the extent of the oncological process and disease stage) and to receive specialized, including high-tech, medical care.

The timeframe for initiating specialized, excluding high-tech, medical care for cancer patients in a medical organization providing care to cancer patients must not exceed 14 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 the malignant neoplasm (in the absence of medical indications for outpatient pathomorphological examinations).

Specialized, including high-tech, medical care is provided by oncologists and radiotherapists in an oncological dispensary or medical organizations providing medical care to patients with oncological diseases, having a license, the necessary material and technical base, certified specialists, in inpatient and day-care 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 cancer patients, the medical examination and treatment strategy is determined by a concilium of oncologists and radiotherapists, with the involvement of other specialist physicians if necessary. The decision of the medical concilium is formalized in a protocol, signed by the participants of the concilium, and entered into the patient's medical documentation.

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

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

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

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

Indications for planned hospitalization in a medical organization are:

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

2) the presence of indications for specialized antitumor treatment (surgical intervention, radiotherapy, including contact, external beam, and other types of radiotherapy, drug therapy, etc.) requiring monitoring in an inpatient or day-care setting.

Indications for discharging a patient from a medical organization are:

1) completion of the course of treatment or one of the stages of specialized, including high-tech, medical care in a 24-hour inpatient unit or day hospital, 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 an inpatient or day-care setting established by a 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 feasibility of transferring the patient to a specialized medical organization is made after a preliminary consultation based on the provided medical documents and/or a preliminary examination of the patient by specialist doctors of the medical organization to which the transfer is planned.

7. Additional Information

Prognostic factors can be divided into 2 groups: those associated with tumor characteristics and those associated with the patient.

Factors associated with the patient include:

• head and neck localization – the highest number of local disease recurrences (62.5%);

• primary tumors located on the scalp are most often larger in size compared to other localizations (10.4% >5 cm; p = 0.0001), as well as distant metastases (8.7%; p = 0.07) (data based on the analysis of 2,104 patients from the SEER database);

• younger patients and/or males more frequently have metastatic lymph node involvement.

Factors associated with tumor characteristics include:

• primary tumor size;

• number of affected lymph nodes.

P. Nghiem et al. analyzed the US National Database, which included 8,044 patients with Merkel cell carcinoma. This allowed the researchers to conclude that clinical prognostic factors include primary tumor size and the number of affected lymph nodes. They showed that the risk of metastasis to regional lymph nodes is directly related to the primary tumor size. Thus, with a primary tumor size of 0.5 cm, the risk is 14%, with an average primary tumor size of 1.7 cm it is 25%, and further increases to 36% or more with a primary tumor size of 6 cm and more [138]. Data obtained from a population of Russian patients also confirm the dependence of the disease course on the primary tumor size: the median progression-free survival with a primary tumor focus size ≤2 cm is 109 months (95% CI 13–204), while the median progression-free survival with a primary tumor size >2 cm is only 10 months (95% CI 4.8–16) [25]. The number of affected lymph nodes is also a predictor of patient survival: 5-year survival is 76% in the absence of lymph node involvement, 50% with 2 affected lymph nodes, 42% with 3–5 lymph nodes, and 24% with ≥6 lymph nodes (p < 0.0001). Therefore, timely diagnosis is extremely important.

Criteria for Evaluating the Quality of Medical Care

Table 11. Criteria for assessing the quality of medical care

Criteria for assessing the quality of primary health care in adults with Merkel cell carcinoma (ICD-10 codes: C44)

Criteria for assessing the quality of specialized medical care in adults with Merkel cell carcinoma (ICD-10 codes: C44)

References

Appendix A1. Working Group Composition

1. Beniamin Yu. Bokhyan, Cand. of Sci. (Med.), Senior Researcher, Department of General Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the Eastern European Sarcoma Group

2. Yana V. Vishnevskaya, Cand. of Sci. (Med.), Researcher, Department of Human Tumor Morbid Anatomy, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the Association of Melanoma Specialists

3. Georgy I. Gafton, Dr. of Sci. (Med.), Head of the Scientific Department of General Oncology and Urology, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health

4. Lev V. Demidov, Dr. of Sci. (Med.), Professor, Head of Surgical Department No. 10 of Tumor Biotherapy, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Chairman of the Association of Melanoma Specialists

5. Vera V. Delektorskaya, Dr. of Sci. (Med.), Head of the Laboratory of Histochemistry and Electron Microscopy, Department of Pathological Anatomy, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the Association of Melanoma Specialists

6. Tatyana T. Kondratyeva, Dr. of Sci. (Med.), Leading Researcher, Laboratory of Clinical Cytology, Department of Pathological Anatomy, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

7. Alla A. Markovich, Cand. of Sci. (Med.), Senior Researcher, Scientific and Advisory Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

8. Valeria V. Nazarova, Oncologist, Surgical Department No. 10 of Tumor Biotherapy, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the Association of Melanoma Specialists

9. Kristina V. Orlova, Cand. of Sci. (Med.), Senior Researcher, Surgical Department No. 10 of Tumor Biotherapy, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the Board of the Association of Melanoma Specialists

10. Igor V. Samoylenko, Cand. of Sci. (Med.), Senior Researcher, Surgical Department No. 10 of Tumor Biotherapy, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the Board of the Association of Melanoma Specialists

11. Erik K. Saribekyan, Dr. of Sci. (Med.), Leading Researcher, Department of Oncology and Reconstructive Plastic Surgery of the Breast and Skin, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

12. Oksana P. Trofimova, Dr. of Sci. (Med.), Leading Researcher, Radiological Department, Department of Radiation Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the Association of Melanoma Specialists

13. Azizzhon D. Zakirkhodjaev, Head of the Department of Oncology and Reconstructive Plastic Surgery of the Breast and Skin, National Center of Oncology of Reproductive Organs, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

14. Aleksandr A. Fedenko, Head of the Drug Treatment of Tumors Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health

15. Larisa V. Bolotina, Head of the Chemotherapy Department, Drug Treatment of Tumors Division, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health

16. Natalia A. Falaleeva, Head of the Department of Drug Treatment of Malignant Neoplasms, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

Conflict of interest: none declared.

Healthcare Organization Section:

1. Alexey A. Nevolskikh, Dr. of Sci. (Med.), Professor, Deputy Director for Medical Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

2. Zhanna V. Khailova, Cand. of Sci. (Med.), Chief Physician of the Clinic, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

3. Tigran G. Gevorkyan, Deputy Director of the Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology.

Medical Rehabilitation Section:

1. Olga A. Obukhova, Cand. of Sci. (Med.), Physical Therapy Doctor, Head of the Rehabilitation Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the European Society for Clinical Nutrition and Metabolism (ESPEN), Russian Society for Parenteral and Enteral Nutrition (RESPEN)

2. Tatyana Yu. Semiglazova, Dr. of Sci. (Med.), Associate Professor, Head of Department – Leading Researcher, Scientific Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Associate Professor of the Department of Oncology, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health

3. Elena V. Filonenko, Dr. of Sci. (Med.), Professor, Oncologist, Head of the Center for Laser and Photodynamic Diagnostics and Therapy of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• oncologists;

• surgeons;

• radiologists;

• medical geneticists;

• dermatovenerologists;

• pathologists;

• clinical laboratory diagnostics physicians;

• medical students, residents, and postgraduate students.

Table 12. Scale for assessing levels of evidence reliability (LER) for diagnostic methods (diagnostic interventions)

Table 13. Scale for evaluating levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitation interventions)

Table 14. Scale for assessing grades of recommendation strength (GRS) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

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

Appendix A3. Reference Materials

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

Table A3-1

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

Appendix B. Physician Action Algorithms

Flowchart 1. Diagnosis and management of a patient with suspected skin tumor (CM)

Appendix C. Patient Information

Recommendations for self-skin examination and primary prevention of skin tumors and melanoma

The main risk factor for skin tumors and melanoma is ultraviolet damage, which occurs due to natural causes (sunburn) or artificial causes (specific occupational conditions or visiting tanning salons).

Different skin types react differently to the same dose of ultraviolet radiation; while some people (with fair skin, the so-called phototype I) always develop sunburns even from minimal doses of UV light (initial stage: skin erythema), others experience minimal harm from solar UV (individuals with tanned or dark skin). The majority of the Russian population has phototypes I–III (i.e., "fair") and is therefore highly sensitive to sunburn.

Prevention of skin sunburn is a key factor in primary prevention. Sunburns during childhood and adolescence make a particularly serious contribution to increasing the risk of melanoma. General recommendations come down to the following simple rules.

1. Use data from mobile applications or weather forecasts regarding the UV index level (the UV index is an indicator characterizing the level of ultraviolet radiation). When the UV index is greater than 2, sun protection is necessary (see table).

Protection measures depending on the UV index

UV index Protection measures

0–2 No protection needed. Outdoor activities are safe

3–7 Protection required. Stay in the shade during midday hours. Wear long-sleeved clothing and a hat. Use sunscreen

8 Enhanced protection required. Stay indoors during midday hours. Remain in the shade when outdoors. Wearing long-sleeved clothing, a hat, and using sunscreen are mandatory

2. Use of a broad-spectrum sunscreen (preventing both UVA and UVB radiation) with an efficacy (SPF [Sun Protecting Factor] for UVB, PPD [Persistent Pigment Darkening] for UVA) appropriate for your skin phototype (i.e., individuals with lighter skin require a higher SPF or PPD). In general, individuals with skin phototype I or II are recommended to use sunscreens with SPF 30–50+ and a maximum PPD of 42.

3. Sunscreens should be combined with other sun protection methods: wearing clothing and UV-blocking glasses, wide-brimmed hats (it is estimated that for a hat's shadow to cover the face and neck, its brim must be at least 10 cm wide), and staying in the shade.

4. Children are additionally recommended to wear special UV-protective clothing.

5. Do not use equipment and lamps for artificial tanning.

Rules for applying sunscreens:

• sunscreens should be applied 30 minutes before going outside to all areas of skin exposed to solar radiation;

• reapplication should be carried out every 2 hours, as well as immediately after swimming and excessive sweating;

• photoprotection specified on the sunscreen label is achieved when applied to the skin at a rate of 2 mg/cm2; applying a smaller amount drastically reduces the degree of skin protection from ultraviolet radiation. To understand the amount of sunscreen required for the labeled skin protection, i.e., 2 mg/cm2, the "teaspoon rule" has been developed [410]:

– arm: 1/2 teaspoon of product;

– head and neck: 1/2 teaspoon;

– leg: 1 teaspoon;

– chest: 1 teaspoon;

– back: 1 teaspoon;

• if it is impossible to apply the required volume of sunscreen all at once, early reapplication (in 15 to 30 minutes) of the cream is necessary;

• sunscreens must be stored at temperatures below +30 °C and must not be used after the expiration date.

Skin examination:

During the examination, special attention should be paid to pigmented spots measuring 4–5 mm or more with asymmetry of shape or color, uneven (scalloped) borders, and uneven pigmentation (various shades of brown). If you notice pigmented spots that exhibit at least 2 of these characteristics, consult a dermatologist or oncologist. It is by no means certain that this nevus will turn out to be malignant, but further evaluation of its condition should be entrusted to a physician. Special attention should be paid to skin lesions in which any characteristics change over time (for example, the area of the pigmented spot increases, or the "mole" becomes thicker, or, conversely, part of the "mole" begins to fade and disappear) — such lesions also require evaluation by a physician specializing in the early diagnosis of skin tumors.

Fig. 1. Skin examination algorithm

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

• start antibiotic therapy: as prescribed by the attending physician.

2. In case of 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 recommended by an oncologist (chemotherapy specialist).

3. In case of diarrhea:

• diet: exclude fatty, spicy, smoked, sweet, dairy, and high-fiber foods. Lean meat, flour products, fermented milk products, and rice water are permitted. Drink plenty of fluids;

• take medications as prescribed by a clinical oncologist (chemotherapy specialist).

4. In case of nausea:

• take medications as prescribed by the oncologists (chemotherapy specialist).

Information for patients receiving anti-CTLA4 and/or PD1/PD-L1 monoclonal antibody therapy

Timely communication with your attending physician and nurse regarding your health status is an essential component of supportive care during treatment.

It is extremely important that any symptoms (adverse events) associated with anti-CTLA4 and/or PD1 monoclonal antibody treatment are identified and treated at their very earliest onset to help prevent progression to more severe grades.

CTLA4 and/or PD1 blockers are designed to help your body's immune system fight the tumor process. The most common side effects you may encounter during treatment result from high immune system activity. Such side effects are called immune-mediated and differ from the side effects you might observe with other cancer treatments (chemotherapy, radiation therapy).

Adverse events that may occur usually arise within the first 12 weeks of treatment, but can also manifest later.

It is very important that you inform your attending physician of any symptoms that occur during treatment with CTLA4 and/or PD1 blockers. Early recognition of side effects enables your attending physician to promptly initiate appropriate therapy and prevent them from progressing to more severe grades.

If you experience any of the symptoms listed below after or during anti-CTLA4 and/or PD1 monoclonal antibody therapy, please inform your attending physician immediately.

Table 15. Potential adverse events following or during anti-CTLA4 and/or PD1 monoclonal antibody therapy

• Please pay special attention to any changes in bowel habits. Keep a daily record of the number of bowel movements. If you experience diarrhea, try to describe it using one of the terms below and determine the urgency level for your specific case:

• loose;

• watery;

• painful;

• bloody;

• mucoid.

Diarrhea does not always present as loose stools. An increased frequency of bowel movements per day, even if the stool is formed, may potentially indicate a problem.

Important! Side effects can occur anywhere from 1 week to several months after starting treatment. If you experience any of these symptoms, tell your attending physician or nurse immediately.

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

Appendix G1. WHO/ECOG Performance Status Scale

Russian title: WHO/ECOG performance status scale

Original title: The ECOG Scale of Performance Status

Source: Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group // Am. J. Clin. Oncol. 1982. Vol. 5, № 6. P. 649–65

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Content and interpretation: