List of Abbreviations
AJCC – American Joint Committee on Cancer
ASCO – American Society of Clinical Oncology
SNO – Society for Neuro-Oncology
ASTRO – American Society for Radiation Oncology
CTCAE – Common Terminology Criteria for Adverse Events
ECOG – Eastern Cooperative Oncology Group
GPA – Graded Prognostic Assessment scale
MAPK – mitogen-activated protein kinase pathway
RECIST – Response Evaluation Criteria in Solid Tumors
UICC – Union for International Cancer Control
IV – intravenous
WHO – World Health Organization
Gy – Gray
TKI – protein kinase inhibitors (ATC code: L01E)
IPI 3 / NIVO 1 – Ipilimumab** 3 mg/kg (on the same day as nivolumab** 1 mg/kg)
IPI 1 / NIVO 3 – Ipilimumab** 1 mg/kg (on the same day as nivolumab** 3 mg/kg)
IPI 1 / PEMBRO 200 – Ipilimumab** 1 mg/kg (on the same day as pembrolizumab** 200 mg)
CT – computed tomography
PT – physical therapy
mAb – monoclonal antibodies (ATC code: L01XC)
ICD-10 – International Classification of Diseases 10th Revision
MRI – magnetic resonance imaging
PET/CT – positron emission tomography combined with computed tomography
SFD – single focal dose
TFD – total focal dose
SRT – stereotactic radiotherapy
SRS – stereotactic radiosurgery
US – ultrasound examination
WBRT – whole-brain radiotherapy
** – 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
BRAF is a human gene (proto-oncogene) encoding the BRAF serine/threonine protein kinase.
BRAF inhibitors (BRAF protein kinase inhibitors, BRAF TKIs) are medicinal products that block the activity of BRAF serine/threonine protein kinase (L01EC B-Raf serine-threonine kinase (BRAF) inhibitors).
KIT is a human gene encoding the mast/stem cell growth factor receptor (SCFR), or KIT protein tyrosine kinase (CD117), a receptor tyrosine kinase encoded by the KIT gene.
KIT inhibitors (KIT protein kinase inhibitors, KIT TKIs) are medicinal products that block KIT receptor activity (L01EA BCR-ABL tyrosine kinase inhibitors).
MEK is an intracellular signaling molecule, a protein kinase also known as MAPK/ERK kinase.
MEK inhibitors (MEK protein kinase inhibitors, MEK TKIs) are medicinal products that block MEK protein kinase activity (L01EE Mitogen-activated protein kinase (MEK) inhibitors).
CTLA4 is cytotoxic T-lymphocyte associated protein 4, also known as CD152. It functions as a receptor with B7.1 or B7.2 serving as its ligand.
PD1 is programmed cell death protein 1.
CTLA4 inhibitor (also referred to in the text as CTLA4 mAb blocker, CTLA4 blocker, anti-CTLA4) – L01FX Other monoclonal antibodies is a monoclonal antibody that blocks inhibitory signals of the CTLA4 cascade.
PD1 blocker (also referred to in the text as PD1 mAb blocker, anti-PD1, aPD1 mAb blocker, PD1 / PDL1 mAb blockers) – L01FF PD-1 / PDL-1 (programmed cell death protein 1 / programmed cell death 1 ligand 1) inhibitors – a monoclonal antibody that blocks the interaction between programmed cell death receptor (PD-1) and its ligands.
Second phase of rehabilitation – rehabilitation in inpatient settings of medical organizations (rehabilitation centers, rehabilitation departments) during the early recovery period of the disease, late rehabilitation period, and the period of residual disease symptoms.
Congenital melanocytic nevi (CMN) represent a benign proliferation of neural crest-derived melanocytes occurring in utero. The primary criterion for CMN classification is their size. Because CMN size increases during childhood proportionally to the child's growth, CMNs are usually classified according to the maximum size the nevus is expected to reach by adulthood. Larger CMN sizes are associated with a higher risk of developing cutaneous melanoma.
Incisional punch biopsy is a method of obtaining a full-thickness skin tissue sample, where lateral resection margins may contain tumor (or nevus) elements. It is performed using a special punch needle (1 to 5 mm in diameter). It is used in exceptional cases when excisional biopsy cannot be applied.
Melanocytic nevus is a benign skin neoplasm whose pathogenesis lies in a developmental defect of epidermal and dermal melanocytes synthesizing the melanin pigment. The main differences between conventional melanocytes located in the basal layer of the epidermis and nevus cells are that nevus cells group in nests either at the epidermal level or in the dermis, whereas epidermal melanocytes are evenly distributed among basal keratinocytes as single units. Nevus cells lack dendritic processes.
First phase of rehabilitation – rehabilitation during the specialized treatment period of the underlying disease (including surgical treatment / chemotherapy / radiation therapy) in departments of medical organizations tailored to the profile of the underlying disease.
Shave resection of skin neoplasms is a method for removing exophytic and flat skin neoplasms in the plane of the skin using a razor blade or scalpel. In case of suspected cutaneous melanoma, it is a suboptimal diagnostic method as it does not reliably determine the thickness of the neoplasm and thus correctly stage the disease.
Prehabilitation – rehabilitation from the moment of diagnosis until the start of treatment (surgical treatment/chemotherapy/radiation therapy).
Radiological response evaluation – evaluation of response to treatment using the results of radiological examinations (computed tomography, magnetic resonance imaging, positron emission tomography, radiography, etc.) in comparison with the results of previous radiological examinations in accordance with one or more response evaluation systems (such as RECIST or WHO).
Resectable cutaneous melanoma and/or resectable cutaneous melanoma metastases – cutaneous melanoma or its metastases (usually metastases to regional lymph nodes) that can be subjected to radical surgical resection R0. The assessment of resectability may be influenced by factors such as the volume (number and size) of metastatic lymph node involvement, relationship with major blood vessels, presence of satellites and in-transit metastases, lymphangitis, etc. The assessment of the resectability of the process is highly subjective and may vary from institution to institution and from surgeon to surgeon.
Stage III rehabilitation – rehabilitation in the early and late rehabilitation periods, and the period of residual manifestations of the disease course in departments (offices) of rehabilitation, physiotherapy, exercise therapy, reflexotherapy, manual therapy, psychotherapy, medical psychology, and speech therapy (defectology) offices providing medical care in outpatient settings, day hospitals, as well as by mobile teams at home (including in sanatorium-resort organizations).
Clinical stage equivalent – assessment of disease extent in accordance with the international UICC/AJCC TNM classification regardless of the medical history of the disease course. In other words, regional lymph node involvement is equivalent to stage III (IIIA, B, C, D – according to the extent), and visceral organ or non-regional lymph node involvement is equivalent to stage IV (IV M1a – skin or non-regional lymph nodes, M1b – lungs, M1c – other internal organs except lungs, M1d – CNS involvement). Hereinafter in the guidelines, approaches to the diagnosis and management of patients will be focused precisely on the stage equivalent (i.e., the currently relevant extent of the disease).
Excisional skin lesion biopsy – a method of obtaining a skin tissue sample in which the lesion is removed totally (completely) with a small (1-3 mm) margin of surrounding healthy tissue. This method of obtaining morphological material is preferred when cutaneous melanoma is suspected.
Epiluminescence microscopy (dermatoscopy) – a non-invasive skin examination technique using a dermatoscope, which usually consists of a magnifier (× 10), a non-polarized light source, a transparent plate, and a liquid medium between the instrument and the skin. Modern dermatoscopes can operate using a liquid medium or instead employ polarized light to compensate for skin surface reflections. When the obtained images or video clips are digitally recorded or processed, the device can be referred to as a digital epiluminescence dermatoscope.
Table A3-1 also lists terms describing procedures in the clinical guideline and possible (closest) terms from the current nomenclature of medical services.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Cutaneous melanoma – a malignant tumor of neuroectodermal origin originating from melanocytes (pigment cells) of the skin [1]. In some cases, in the presence of distant metastases, the primary focus on the skin (или in other organs) cannot be detected (e.g., due to so-called spontaneous regression of the primary tumor or removal of the lesion during a medical or cosmetic manipulation without morphological examination) – such a disease should be designated as melanoma metastases with an unknown primary. Given that melanocytes are normally present in various organs (including the mucous membranes of the gastrointestinal tract, genital tracts, meninges, vascular tunic of the eye, etc.) [2], the primary tumor (melanoma) can arise in any of these organs. In this case, the tumor should be designated as melanoma of the corresponding organ, for example, melanoma of the ileal mucosa or uveal melanoma.
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
There is no single etiological factor for the development of melanoma. The most significant risk factor for sporadic (non-hereditary) forms of cutaneous melanoma should be considered exposure of the skin to ultraviolet B radiation (wavelength 290–320 nm) and ultraviolet A radiation (wavelength 320–400 nm). At the same time, skin sensitivity to ultraviolet exposure varies among individuals and can be classified into 6 types, where types 1 and 2 differ by the highest sensitivity (and, accordingly, the probability of sunburn), and types 5 and 6 – by the lowest [3]. Other risk factors are also considered to be the presence of more than 10 dysplastic nevi, the presence of more than 100 common acquired nevi, red hair (usually associated with skin phototype I), and intense intermittent exposure to solar ultraviolet radiation (sunburns) in childhood [4-6]. Epidemiological data show that the risk of melanoma associated with ultraviolet irradiation is highest in people with intermittent sun exposure and sunburns in childhood [7]. Risk factors to note also include the presence of a giant or large congenital nevus (covering more than 5% of the body surface area), a family history of cutaneous melanoma, a personal history of cutaneous melanoma, dysplastic nevus syndrome, the use of PUVA therapy (for psoriasis and other chronic dermatoses), xeroderma pigmentosum, and congenital or acquired immunodeficiency (e.g., after organ transplantation or in other conditions requiring immunosuppressants) [8]. Risk factors for melanoma of other sites (e.g., mucosal melanoma, acral melanoma, uveal melanoma) have not been sufficiently studied [9-12].
The majority of melanoma cases in children are sporadic, more frequently associated with ultraviolet (UV) radiation, and in its biological characteristics, this variant of melanoma is closest to adult melanoma [13,14].
The etiology of cutaneous melanoma in children is a subject of discussion. It is quite likely that there is an interaction between inherited and environmental factors. However, there are several known risk factors in children, which include congenital giant melanocytic nevus (CGMN) [15], retinoblastoma, xeroderma pigmentosum and cases of familial melanoma [16], as well as congenital or acquired immunodeficiency (e.g., after organ transplantation or in other conditions requiring immunosuppressants) [8].
For example, in a study of adolescents aged 15–19 years, it was found that the risk of developing melanoma is 34 times higher in children with 100+ nevi on the skin and 15 times higher in children with 10+ large nevi with a diameter > 5 mm [13,17]. In a study conducted in Australia, children under 15 years of age were examined. In this study, Whiteman et al. found that the presence of numerous nevi, facial freckles, increased skin sensitivity to ultraviolet exposure, and a lower tanning capacity indicate a higher incidence of melanoma development [18].
Melanoma in children is traditionally subdivided into three main variants, which differ from each other etiologically, by mechanisms of carcinogenesis, and by clinical course [19,20]:
1) Melanoma arising on the background of CGMN [21] – a rare variant of melanoma with the most unfavorable prognosis;
2) Spitzoid melanoma – it accounts for approximately half of all melanoma cases in adolescents and is characterized by a favorable course;
3) Cutaneous melanoma arising de novo – about 40-50% of all cutaneous melanomas in children, characterized by a nodular growth type and aggressive course, and in its biological and molecular genetic characteristics is close to adult cutaneous melanoma. The distinction between these subtypes is important to understand because they have distinct risk factors and morphological characteristics.
Cutaneous melanoma arising de novo demonstrates genetic similarity to cutaneous melanoma in adults, and in 40-60% of cases, a mutation in the BRAF gene is present. Melanoma arising on the background of CGMN has a lower frequency of UV-associated mutations.
Some mechanisms of melanoma carcinogenesis have been studied in vitro and in vivo: the ability of ultraviolet radiation to induce and stimulate melanoma growth has also been demonstrated in several animal models. Ultraviolet radiation may contribute to melanomagenesis through various pathways. Mutations characteristic of ultraviolet irradiation (especially ultraviolet B-induced mutations) are found in genes involved in melanoma development. Ultraviolet radiation inactivates the p16INK4A tumor suppressor protein, thereby promoting melanoma progression. Ultraviolet radiation decreases the expression of E- and P-cadherin on both normal and malignant melanocytes, enhancing $\beta$-catenin signaling, which promotes the malignant phenotype in melanocytes and disrupts cell adhesion, which in turn allows melanoma cells to detach from neighboring keratinocytes, thereby promoting an invasive phenotype [7].
1.3 Epidemiology of the Disease or Condition
In 2023, 13,270 people were diagnosed with cutaneous melanoma in the Russian Federation [22]. In 2023, the crude incidence rate (both sexes) was 9.07 per 100,000 population (in 2019 – 6.94), and the age-standardized rate was 5.15 per 100,000 population (in 2019 – 4.89) [22]. The age-standardized incidence rate was 4.94 and 5.47 per 100,000 population in men and women, respectively. In the structure of incidence, cutaneous melanoma in 2023 accounted for 1.7% in men and 2.2% in women. The average annual growth rate of the crude incidence rate over 10 years was 3.28% in men and 2.61% in women. The average age of patients at diagnosis was 61.9 years (both sexes), 61.5 years (men), and 62.1 years (women) [22].
In 2023, 1,539 men and 1,552 women died from cutaneous melanoma in Russia; the crude mortality rate (both sexes) was 2.09 per 100,000 population (2.45 in 2019), and the age-standardized rate was 1.13 per 100,000 population (1.44 in men and 0.94 in women) [22]. The average annual growth rate of mortality over the 2013–2023 period was negative at -1.33% (a 12.3% decrease in mortality over 10 years for the crude rate and 24.93% for the age-standardized rate).
The average age at death was 65.6 years (both sexes), 64.4 years (men), and 66.7 years (women) [22].
In 2023, the stage distribution of newly diagnosed cases was as follows: stage I – 42.5%, stage II – 37.8%, stage III – 10.8%, stage IV – 7.9%, and stage unknown in 1.0%. Among newly diagnosed patients, the disease was detected actively in 27.8%. One-year mortality was 6.9% (compared to 12.3% in 2013) [23].
At the end of 2022, there were 106,061 patients under active follow-up (72.7 per 100,000 population), of whom 65,123 patients (61.4%) had been followed for 5 years or more. The patient accumulation index was 10.0, and mortality was 2.8% (compared to 4.3% in 2011). Meanwhile, according to available reporting forms, in 2022, 88.5% of patients with cutaneous melanoma (among those eligible for radical treatment) received surgical treatment only [23].
Melanoma is one of the most aggressive forms of skin tumors and is the second leading cause of malignancies in adolescents and young adults aged 15–29 years [24]. The incidence of melanoma increases sharply with age, from 1.1 per million in children aged 1 to 4 years to 10.4 per million in those aged 15 to 19 years [25]. Since the 1970s, the incidence of pediatric melanoma has increased with an average annual percent change of 2–2.9% [16,26,27]. However, updated analyses of the SEER (Surveillance, Epidemiology, and End Results) database demonstrate a downward trend in overall incidence between 2000 and 2010 [28,29]. According to the SEER database, 4 children per 1 million population are diagnosed with melanoma annually in the USA, and the majority of children are older than 10 years [30]. Campbell et al. noted an 11.6% annual decrease in melanoma incidence in children under 20 years of age between 2004 and 2010 [29]. There are also differences by sex, with females showing a slightly higher incidence rate [29]. Girls older than 4 years more frequently present with melanoma of the lower trunk, whereas boys older than 10 years more frequently present with melanoma of the head and neck [26].
In 2022, 35 patients aged up to 19 years (0–19 years) were diagnosed with cutaneous melanoma in the Russian Federation [31,32], with only 4 patients aged up to 14 years (2 girls and 2 boys) — see also Table 1. In the structure of incidence in 2023, cutaneous melanoma accounted for less than 1% in both boys and girls across both younger age groups, and only in the 15–19 age group of adolescents did it reach 2.3% [31,32].
In 2023, 4 patients aged 0–19 years died from cutaneous melanoma (3 boys and 1 girl), while no deaths from melanoma were registered in children under 5 years of age. The table below (see Table 2) presents data on pediatric melanoma incidence in Russia in 2023 [31,32].
Table 1. Incidence of cutaneous melanoma in Russia by sex and age among children in 2023
Sex/age | 0-4 | 5-9 | 10-14 | 15-19 |
|---|---|---|---|---|
Both sexes | 1 (0.01 per 100 thousand) | 0 (0.00 per 100 thousand) | 3 (0.03 per 100 thousand) | 31 (0.4 per 100 thousand) |
Boys | 0 (0.00 per 100 thousand) | 0 (0.00 per 100 thousand) | 2 (0.00 per 100 thousand) | 14 (0.38 per 100 thousand) |
Girls | 1 (0.03 per 100 thousand) | 0 (0.00 per 100 thousand) | 1 (0.02 per 100 thousand) | 21 (0.56 per 100 thousand) |
Table 2. Mortality from cutaneous melanoma in Russia by sex and age among children in 2023
Sex/age | 0-4 | 5-9 | 10-14 | 15-19 |
|---|---|---|---|---|
Both sexes | 0 (0.01 per 100 thousand) | 1 (0.01 per 100 thousand) | 1 (0.01 per 100 thousand) | 2 (0.03 per 100 thousand) |
Boys | 0 (0.00 per 100 thousand) | 0 (0.00 per 100 thousand) | 1 (0.02 per 100 thousand) | 2 (0.05 per 100 thousand) |
Girls | 1 (0.03 per 100 thousand) | 1 (0.02 per 100 thousand) | 0 (0.00 per 100 thousand) | 0 (0.05 per 100 thousand) |
1.4 Features of Coding the Disease or Condition
According to the International Statistical Classification of Diseases and Related Health Problems (hereinafter referred to as ICD-10), such tumors are classified according to the organ of primary origin; for example, melanoma of the ileum has the code C17.2, choroidal melanoma of the eye has C69.3, and cutaneous melanoma has C43.
Malignant melanoma of skin (C43, C51, C60.9, C63.2) [33]:
C43.0 Malignant melanoma of lip;
C43.1 Malignant melanoma of eyelid, including canthus;
C43.2 Malignant melanoma of ear and external auricular canal;
C43.3 Malignant melanoma of other and unspecified parts of face;
C43.4 Malignant melanoma of scalp and neck;
C43.5 Malignant melanoma of trunk (including skin of perianal region, anus, and border zone, breast);
C43.6 Malignant melanoma of upper limb, including shoulder region;
C43.7 Malignant melanoma of lower limb, including hip region;
C43.8 Malignant melanoma of skin, overlapping; [overlapping lesion of skin];
C43.9 Malignant melanoma of skin, unspecified;
C51 Malignant neoplasm of vulva;
C60.9 Malignant neoplasm of penis, unspecified;
C63.2 Malignant neoplasm of scrotum;
C69.0 Malignant neoplasm of conjunctiva.
Melanoma of unknown primary origin:
C77 Secondary and unspecified malignant neoplasm of lymph nodes (for cases of newly diagnosed melanoma metastases in lymph nodes without an identified primary site);
C78 Secondary malignant neoplasm of respiratory and digestive organs;
C79 Secondary malignant neoplasm of other sites.
Mucosal melanoma:
C00–C14 Malignant neoplasms of lip, oral cavity, and pharynx;
C15–C26 Malignant neoplasms of digestive organs;
C30–C32: Malignant neoplasm of nasal cavity and middle ear, Malignant neoplasm of accessory sinuses, Malignant neoplasm of larynx;
C51–C53 Malignant neoplasms of female genital organs;
C60.9 Malignant neoplasms of penis, unspecified.
Melanoma in situ:
D03.0 Melanoma in situ of lip;
D03.1 Melanoma in situ of eyelid, including canthus;
D03.2 Melanoma in situ of ear and external auricular canal;
D03.3 Melanoma in situ of other and unspecified parts of face;
D03.4 Melanoma in situ of scalp and neck;
D03.5 Melanoma in situ of trunk;
D03.6 Melanoma in situ of upper limb, including shoulder girdle;
D03.7 Melanoma in situ of lower limb, including hip;
D03.8 Melanoma in situ of other sites;
D03.9 Melanoma in situ, unspecified site.
1.5 Classification of the disease or condition
1.5.1. International Histological Classification
International Histological Classification of Cutaneous Melanocytic Tumors [34]:
Melanocytic tumors of skin with intermittent sun exposure:
melanoma on skin with low cumulative solar damage (superficial spreading melanoma): 8743/3
simple lentigo and lentiginous melanocytic nevus 8742/0 (new code)
junctional nevus 8740/0
compound nevus 8760/0
dermal nevus 8750/0
dysplastic nevus 8727/0
nevus spilus 8720/0
nevi of special sites (breast, axilla, scalp, and ear):
halo nevus 8723/0
Meyerson nevus 8720/0
recurrent nevus
deep penetrating nevus 8720/0
pigmented epithelioid melanocytoma 8780/1 (new code)
combined nevus, including BAP1-inactivated nevus/melanocytoma 8720/0
Melanocytic tumors arising on skin with chronic sun-induced damage:
lentigo maligna melanoma 8742/3
desmoplastic melanoma 8745/3
Spitzoid tumors:
malignant Spitz tumor (Spitz melanoma) 8770/3
Spitz nevus 8770/0
pigmented spindle cell nevus (Reed nevus) 8770/0
Melanocytic tumors arising on acral skin:
acral melanoma 8744/3
acral nevus 8744/0 (new code)
Melanocytic tumors of the genital and mucosal sites:
mucosal melanomas (genitalia, oral cavity, nasal sinuses): 8720/3
mucosal lentiginous melanoma 8746/3
mucosal nodular melanoma 8721/3
genital nevus 8720/0
Melanocytic tumors derived from blue nevus:
melanoma arising from blue nevus 8780/3
blue nevus, NOS 8780/0
cellular blue nevus 8790/0
mongolian spot
nevus of Ito
nevus of Ota
Melanocytic tumors arising from congenital nevi:
melanoma arising from giant congenital nevus 8761/3
congenital melanocytic nevus 8761/0
proliferative nodules in congenital nevus 8762/1
Melanocytic tumors of the eye:
uveal melanoma
epithelioid cell melanoma 8771/3
spindle cell melanoma, type A 8773/3
spindle cell melanoma, type B 8774/3
conjunctival melanoma
melanoma, NOS 8720/3
conjunctival primary acquired melanosis with atypia/melanoma in situ 8720/2
conjunctival nevus 8720/0
Nodular, nevoid, and metastatic melanoma:
nodular melanoma 8721/3
nevoid melanoma 8720/3
metastatic melanoma 8720/6
1.5.2. Staging
TNM staging of cutaneous melanoma according to the AJCC/UICC 8th edition (2017) [35,36]. Histological confirmation is mandatory for melanoma staging. Assessment of lymph node status for staging purposes is performed using clinical examination, imaging studies, and sentinel lymph node biopsy.
The T category reflects the extent of the primary tumor. T categorization is only possible after excision of the primary tumor and its histological examination (Table 3).
Table 3. T category (primary tumor)
T criterion | Breslow tumor thickness | Primary tumor ulceration |
|---|---|---|
Tx: Primary tumor thickness cannot be assessed (e.g., tumor removed by curettage, shave biopsy, or partial regression of melanoma) | Not applicable | Not applicable |
T0: No evidence of primary tumor (e.g., primary site not identified or complete regression of melanoma) | Not applicable | Not applicable |
Tis: Melanoma in situ (Clark level of invasion I) (atypical melanocytic hyperplasia, severe melanocytic dysplasia, non-invasive malignant tumor) | Not applicable | Not applicable |
T1 | ≤ 1.0 mm | Unknown or not determined |
T1a | < 0.8 mm | Without ulceration |
T1b | < 0.8 mm | With ulceration |
0.8–1.0 mm | With or without ulceration | |
T2 | > 1.0 and ≤ 2.0 mm | Unknown or not determined |
T2a | > 1.0 and ≤ 2.0 mm | Without ulceration |
T2b | > 1.0 and ≤ 2.0 mm | With ulceration |
T3 | > 2.0 and ≤ 4.0 mm | Unknown or not determined |
T3a | > 2.0 and ≤ 4.0 mm | Without ulceration |
T3b | > 2.0 and ≤ 4.0 mm | With ulceration |
T4 | > 4.0 mm | Unknown or not determined |
T4a | > 4.0 mm | Without ulceration |
T4b | > 4.0 mm | With ulceration |
The N category indicates the presence or absence of metastases in regional lymph nodes (Table 4).
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.
Table 4. N category (regional lymph node involvement)
N category (corresponds to pN) | Number of involved lymph nodes | Transit, satellite, or microsatellite metastases |
|---|---|---|
Nx1 | Regional lymph nodes cannot be assessed | Not applicable |
N0 | No evidence of regional lymph node involvement | Absent |
N1 | One involved regional lymph node or presence of transit, satellite, or microsatellite metastases | |
N1a | One involved clinically occult regional lymph node (i.e., detected by sentinel lymph node biopsy) | Absent |
N1b | One involved clinically apparent regional lymph node | Absent |
N1c | No regional lymph node metastases | Present |
N2 | Two or three involved regional lymph nodes, or one involved regional lymph node combined with transit, satellite, or microsatellite metastases | |
N2a | Two or three involved clinically occult regional lymph nodes (i.e., detected by sentinel lymph node biopsy) | Absent |
N2b | Two or three involved clinically apparent regional lymph nodes | Absent |
N2c | One involved clinically occult or apparent regional lymph node | Present |
N3 | Four or more involved regional lymph nodes, or two or more involved regional lymph nodes combined with transit, satellite, or microsatellite metastases | |
N3a | Four or more involved clinically occult regional lymph nodes (i.e., detected by sentinel lymph node biopsy) | Absent |
N3b | Four or more involved regional lymph nodes, with at least one clinically apparent, or matted lymph nodes | Absent |
N3c | Two or more clinically occult or apparent regional lymph nodes, or regional lymph node matted masses | Present |
1 In accordance with UICC classification rules, clinical or radiological methods are acceptable for assessing regional nodes, whereas AJCC rules strictly recommend morphological assessment of regional lymph nodes and designating Nx whenever sentinel lymph node biopsy was not performed or regional lymph nodes were previously removed for another reason. Exception: morphological staging is not required for T1 melanoma; clinical data should be used.
Note. Satellites are tumor deposits or nodules (macro- or microscopic) within 2 cm of the primary tumor. Transit (in-transit) metastases are metastases in the skin or subcutaneous tissue located more than 2 cm from the primary tumor, but not extending beyond the regional lymph nodes.
Isolated tumor cells, which are single cells or cell clusters measuring no more than 0.2 mm in greatest dimension and detectable by routine hematoxylin and eosin staining or immunohistochemistry in regional lymph nodes, are classified as metastases (N1, N2, or N3 depending on the number of involved lymph nodes).
Anatomical landmarks for defining 4 cm wide watershed areas are provided below (Table 5).
Table 5. Anatomical landmarks of watershed areas for defining regional lymph node basins
Regions | Boundary line (4 cm wide) |
|---|---|
Left and right halves of the body | Midline of the body |
Head and neck / chest wall | Clavicle – acromion – upper edge of the shoulder |
Chest wall / upper extremity | Shoulder – axilla – shoulder |
Chest wall / abdomen, lower back, or buttocks | Anteriorly: midpoint between the umbilicus and costal margin; posteriorly: lower border of the 12th thoracic vertebra (transverse process) |
Abdomen, lower back, or buttocks / lower extremity | Inguinal crease – greater trochanter – gluteal fold |
If metastases are detected in lymph nodes outside the specified regional metastatic zones, they should be classified as distant metastases.
M category characterizes the presence or absence of distant metastases (Table 6).
Table 6. M category (distant metastases)
M category | Anatomical site of metastases | Blood lactate dehydrogenase activity level |
|---|---|---|
M0 | No distant metastases | Not applicable |
M1 | Distant metastases present | – |
M1a | Distant metastases to the skin, soft tissues (including muscle), and/ype or non-regional lymph nodes | Not specified or unknown |
M1a(0) | Not elevated | |
M1a(1) | Elevated | |
M1b | Distant metastases to the lungs with or without metastases corresponding to M1a sites | Not specified or unknown |
M1b(0) | Not elevated | |
M1b(1) | Elevated | |
M1c | Distant metastases to visceral organs, excluding the central nervous system, with or without metastases corresponding to M1a and M1b sites | Not specified or unknown |
M1c(0) | Not elevated | |
M1c(1) | Elevated | |
M1d | Distant metastases to the central nervous system | Not specified or unknown |
M1d(0) | Not elevated | |
M1d(1) | Elevated |
Stage groupings of criteria for melanoma are presented below (Table 7).
Table 7. TNM stage grouping for cutaneous melanoma
T | N | M | Stage |
|---|---|---|---|
Tis | N02 | M0 | 0 |
T1a | N0 | M0 | IA |
T1b | N0 | M0 | IA |
T2a | N0 | M0 | IB |
T2b | N0 | M0 | IIA |
T3a | N0 | M0 | IIA |
T3b | N0 | M0 | IIB |
T4a | N0 | M0 | IIB |
T4b | N0 | M0 | IIC |
T0 | N1b, N1c | M0 | IIIB |
T0 | N2b, N2c, N3b, or N3c | M0 | IIIC |
T1a/b–T2a | N1a or N2a | M0 | IIIA |
T1a/b–T2a | N1b/c or N2b | M0 | IIIB |
T2b/T3a | N1a–N2b | M0 | IIIB |
T1a–T3a | N2c or N3a/b/c | M0 | IIIC |
T3b/T4a | Any N category ≥ N1 | M0 | IIIC |
T4b | N1a–N2c | M0 | IIIC |
T4b | N3a/b/c | M0 | IIID |
Any T, Tis | Any N category | M1 | IV |
2 For Tis or T1 stage, morphological verification of lymph node status is not required. Clinical assessment of lymph node status is permitted for pathologic staging.
Cutaneous melanoma metastases without an identified primary tumor in peripheral lymph nodes of a single region should be staged as stage III (IIIB (T0N1b, T0N1c) or IIIC (T0N2b, N2c, N3b, or N3c)).
An online calculator for determining pTNM stage according to the AJCC/UICC 8th edition TNM classification is available at http://melanoma.pro/site/calctnm.
Staging of upper aerodigestive tract melanoma (C00–06, C10–14, C30–32) according to the 8th edition UICC TNM classification (2017) [36].
Histological confirmation is mandatory for melanoma staging. Assessment of lymph node status for staging is performed using clinical examination and instrumental studies.
T category reflects the extent of the primary tumor:
Tx – primary tumor cannot be assessed (including cases of spontaneous tumor regression and errors during surgical tumor removal);
T0 – no evidence of primary tumor;
Tis – not applicable;
T1 – not applicable;
T2 – not applicable;
T3 – tumor is limited to the epithelium and/or submucosa (mucosal disease);
T4a – tumor invades the underlying soft tissue, cartilage, bone, or overlying skin;
T4b – tumor invades any of the following structures: brain, dura mater, skull base, cranial nerves of the skull base (IX, X, XI, XII), masticator space, prevertebral space, mediastinum.
Mucosal melanoma is an aggressive tumor, therefore T1 and T2 criteria, as well as stages I and II, are omitted.
N category indicates the presence or absence of regional lymph node metastases:
Nx – regional lymph nodes cannot be assessed;
N0 – no regional lymph node metastases;
N1 – regional lymph node metastases present.
M category characterizes the presence or absence of distant metastases:
M0 – no distant metastases;
M1 – presence of distant metastases.
The TNM staging groups for mucosal melanoma are shown below (Table 8).
Table 8. TNM stage grouping for mucosal melanoma of the upper aerodigestive tract
Stage | T | N | M |
|---|---|---|---|
III | T3 | N0 | M0 |
IVA | T4a T3, T4a | N0 N1 | M0 M0 |
IVB | T4b | Any | M0 |
IVC | Any | Any | M1 |
1.6 Clinical presentation of the disease or condition
In most cases, the clinical diagnosis of primary cutaneous melanoma does not present difficulties for a trained specialist [37].
There are 4 most common clinical forms of melanoma: superficial spreading, nodular, lentigo maligna, and acral lentiginous.
Superficial spreading melanoma accounts for about 70% of cutaneous melanoma cases and generally has a relatively favorable prognosis, which is associated with the presence of 2 phases in its development. The radial growth phase is characterized by a low metastatic potential (Clark level II of invasion) and may last for several years. Then the melanoma transitions into the vertical growth phase, which is characterized by tumor cell invasion into the reticular and subcutaneous fat layers and a high metastatic potential. Superficial spreading melanoma develops on outwardly unchanged skin – de novo or against the background of a pigmented nevus in the form of a small, flat, dark, almost black nodule, 1–3 mm in diameter, with gradual development of induration and border changes; its surface becomes uneven, irregular in outline, and it is easily traumatized and bleeds. Tumor growth is often accompanied by subjective sensations such as pruritus and discomfort ("tumor sensation").
Nodular melanoma is characterized by primary vertical growth and is considered the most unfavorable tumor type in terms of prognosis. The nodular variant of melanoma presents as a firm nodule with an uneven surface of varying sizes; its surface ulcerates, bleeds, and becomes crusted.
Lentigo maligna melanoma, like superficial spreading melanoma, undergoes a biphasic process in its evolution, and the radial growth phase in this tumor type can last much longer – 10 years or more. Conditionally, 2 stages can be distinguished in the radial growth phase: the 1st stage is non-invasive and corresponds to lentigo maligna, an obligate precancerous condition. Next, invasive growth begins and lentigo maligna transitions to lentigo maligna melanoma; the rate of invasion in this case is less pronounced than in superficial spreading melanoma. Vertical growth into the deep dermis and subcutaneous fat layer is also characteristic of lentigo maligna melanoma, but it may take several years rather than months as in superficial spreading melanoma, which explains the lack of noticeable changes in the biological course of the tumor and the low risk of metastasis development. The prognosis for this form of melanoma is more favorable than for superficial spreading.
Acral lentiginous melanoma is localized on the distal parts of the extremities – the skin of the hands and feet, in the nail bed, and the proximal nail fold. It is also characterized by a biphasic development: a horizontal growth phase, which corresponds to the biological behavior of lentigo maligna melanoma, and a vertical invasive growth phase. This tumor type is distinguished by a more aggressive clinical course, metastasizing more frequently and earlier; furthermore, the specific localization hinders tumor visualization, and in most cases, it is diagnosed already at the invasive growth stage.
In clinical and anamnestical analysis, the presentation of superficial spreading cutaneous melanoma is best described by the classical ABCDE acronym:
A (asymmetry) – superficial spreading cutaneous melanoma appears as a pigmented lesion characterized by asymmetry: if an imaginary line is drawn through the lesion, one half does not match the other in shape.
B (border) – the borders of cutaneous melanoma are uneven in character: they may be irregular, indistinct, and have "geographic" outlines.
C (color) – superficial spreading cutaneous melanoma is characterized by polychromasia – the presence of multiple colors within a single lesion.
D (diameter) – the size of superficial spreading cutaneous melanoma most often exceeds 0.5 cm. E (evolution or elevation) – cutaneous melanoma is always characterized by some evolution over time.
The ABCDE rule is not applicable to small melanoma lesions (less than 0.5 cm) or to nodular melanoma, since the developing nodule may initially be symmetrical, with smooth borders, homogeneous black or blue-black color, and any diameter. The evolution sign of the lesion, however, remains relevant – patients note the growth of the nodule over time, and sometimes pain or a burning sensation appearing in the tumor area. Rarer clinical forms of melanoma (lentigo maligna melanoma, acral lentiginous melanoma, subungual melanoma, amelanotic melanoma, etc.) may cause difficulties in clinical diagnosis, therefore additional non-invasive diagnostic methods (dermatoscopy) performed by trained specialists are recommended [37]. In case of difficulty in interpreting the obtained data or ambiguity of the dermatoscopic picture, a biopsy of the neoplasm is indicated (see section 2.5).
Another method for the clinical diagnosis of cutaneous melanoma is inter-individual comparative analysis ("ugly duckling" and "Little Red Riding Hood" signs). The "ugly duckling" sign is based on a general assessment of all existing skin lesions and a clear distinction of melanoma from existing benign pigmented lesions. Another variant of the "ugly duckling" sign is the detection of a single lesion changing over time in a specific topographical area, especially if the dynamic changes contradict the stereotypical evolutionary and age-related features of benign cutaneous pigmented tumors. The "Little Red Riding Hood" sign is characterized by dermoscopic differences between a malignant neoplasm and benign nevi in a clinically uniform picture [38,39].
In some cases, melanoma presents with lymph node enlargement, which is initially misdiagnosed as lymphadenitis, lymphoma, or metastasis of a cancer with an unidentified primary site. Timely fine-needle aspiration biopsy or core needle biopsy (sometimes followed by immunohistochemical or immunocytochemical analysis) of the enlarged lymph node helps differentiate other causes of lymphadenopathy from melanoma metastases.
When melanoma is localized in the nasal cavity mucosa and paranasal sinuses, the most frequent symptoms are nasal congestion and epistaxis. Diplopia, exophthalmos, pain, and facial contour deformation are less common. When melanoma is localized in the oral mucosa, the disease is clinically asymptomatic in early stages, while pain, ulceration, and bleeding appear in advanced stages.
Clinical presentation features of cutaneous melanoma in children.
Cordoro et al. found that in 60% of children under 10 years of age and 40% of adolescents, the clinical presentation of melanoma did not match the traditional ABCDE criteria [14]. Children exhibited lesional symmetry, regular borders, uniform color, and a diameter of ≤ 6 mm. Thus, Cordoro and colleagues [14] proposed the following criteria, which are more specific for pediatric melanoma: A = amelanotic; B = bleeding, bump (nodule); C = color uniformity; D = de novo, any diameter; E = evolution of the lesion. Melanomas in children tend to be amelanotic and nodular, presenting as a rapidly growing tumor that may mimic a pyogenic granuloma, keloid scar, or wart rather than a changing nevus [14,40-42].
Another mnemonic is CUP, which includes color uniformity (pink/red) (C - color uniformity (pink/red)), presence of ulceration and upward thickening (U - ulceration and upward thickening), presence of pyogenic granuloma-like features and pop-up of new lesions (P - pyogenic granuloma-like lesions and pop-up of new lesions) [43].
A particular challenge in children is the clinical and instrumental differential diagnosis of Spitz nevus and melanoma arising from a Spitz nevus.
There is a wide spectrum of atypical melanocytic neoplasms, and the distinction between Spitz nevus, atypical Spitz tumor, Spitzoid melanoma, and melanocytic tumors of uncertain malignant potential is controversial with low diagnostic agreement among dermatopathologists [44-46]. Many of these melanocytic lesions were initially misdiagnosed as benign and only later recognized as malignant after recurrence. In one study, 35% of cases initially classified as Spitz nevus were reclassified as epithelioid or spindle cell cutaneous melanoma upon review [45]. Due to the difficulty in differentiating between benign and malignant melanocytic neoplasms in children, all histological slides must be evaluated by pathologists (dermatopathologists) experienced in diagnosing such lesions.
A Spitz nevus is a specific type of benign melanocytic neoplasm that most commonly develops in children. Classically, a Spitz nevus presents as a solitary pink, red, or brown papule, most frequently on the face (especially in young children) or lower extremity. Initial growth tends to be rapid, which can cause anxiety for parents and physicians. The surface may be smooth or verrucous, leading to frequent misdiagnosis as a common wart, pyogenic granuloma, dermatofibroma, or juvenile xanthogranuloma [47,48].
A specific clinical picture that extremely complicates early diagnosis is observed when melanoma arises within a congenital giant melanocytic nevus. Congenital melanocytic nevi are classically defined as present at birth. Multiple recent clinical studies indicate that CMNs occur in approximately 2-3% of newborns regardless of ethnicity [49,50]. While small and medium CMNs are relatively common, large or giant CMNs occur in only about 1 in 20,000 to 50,000 newborns. Congenital nevi are classified according to their adult size as the child grows: small congenital nevi (less than 1.5 cm); medium congenital nevi (1.5 to 20 cm); large congenital nevi (20 to 40 cm); and giant congenital nevi (40 to 60 cm and greater than 60 cm) [21]. The risk of melanoma development in small and medium CMNs is < 1% over a lifetime [51,52]. Based on several large prospective and retrospective cohort studies, the risk of developing melanoma (cutaneous or extracutaneous) associated with a large or giant CMN is considered to be 5% or greater [53]. Melanoma development is most likely in patients with CMNs where the projected adult nevus size exceeds 40-60 cm in diameter, accounting for about 75% of CMN-associated melanomas, with melanomas more frequently arising deep in the dermis or subcutis and presenting as a growing nodule [21].
2. Diagnostics, medical indications and contraindications for diagnostic methods
Criteria for establishing the diagnosis/condition:
history data;
physical examination data and, in some cases, dermoscopic examination data;
vital pathomorphological examination data of biopsy material.
The clinical diagnosis is based on a combination of the results of 3 analyses of any pigmented lesion:
visual analysis of each lesion individually: naked-eye examination assesses the so-called A (asymmetry), B (border irregularity), C (color variation), and D (diameter of 5 mm or more) criteria that indicate suspicious melanocytic neoplasms (the ABCD rule);
inter-individual comparative analysis: search for a pigmented lesion that looks different from the others in the same patient (the "ugly duckling" sign);
chronological analysis of changes: search for rapid and recent changes in a given pigmented lesion (E for evolution), which can be confirmed by the patient or documented by comparison with previous photographs [38,39].
Below is the evaluation plan depending on the results of the pigmented skin lesion biopsy and clinical examination (Table 9). Recommendations on the use of medical interventions themselves are presented in the respective sections.
Table 9. Evaluation plan depending on the results of skin pigmented lesion biopsy and clinical examination
Disease stage | Physical examination | Instrumental diagnostics | Laboratory diagnostics | Sentinel lymph node biopsy | Molecular genetic testing |
|---|---|---|---|---|---|
0, I | Yes |
| No | Yes (if tumor thickness is 0.8 mm or greater) | No |
IIA | Yes |
| No | Yes | No |
IIB, IIC, III | Yes |
| General clinical and biochemical blood tests if necessary | Yes (for stages IIB, IIC) | Molecular genetic testing for BRAF gene mutations is mandatory (for stage III) |
IV | Yes |
|
| Not applicable | Molecular genetic testing for BRAF gene mutations is mandatory (for cutaneous melanoma); in the absence of a BRAF mutation, molecular genetic testing for KIT gene mutations |
2.1 Complaints and Anamnesis
It is recommended to collect complaints and medical history in all patients to identify risk factors and factors that may influence the choice of treatment tactics, diagnostic methods, and secondary prevention [54,55].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: key risk factors for cutaneous melanoma are provided in subsection 1.2 "Etiology and Pathogenesis".
Most commonly, the patient presents with a complaint that a "mole" has begun to change, noting growth, altered border configuration, and the appearance of multiple color shades within the neoplasm. Another frequent complaint is itching, burning, or subjective discomfort in the area of a pre-existing or de novo neoplasm.
In children, nevus modification should not be used as the sole criterion for its removal. The natural evolution of benign pigmented lesions in children may at some point meet melanoma diagnostic criteria, specifically the "ABCDE" algorithm (asymmetry, border irregularity, color variegation, diameter > 6 mm, evolution) [56]. It should be remembered to modify the ABCDE rule for pediatric melanoma: A = amelanotic; B = bleeding, bump (nodule); C = color uniformity; D = de novo, any diameter; E = evolution of the lesion. Melanomas in children tend to be amelanotic and nodular, presenting as a rapidly growing tumor that may mimic a pyogenic granuloma, keloid scar, or wart rather than a changing nevus [14,40-42].
2.2 Physical Examination
It is recommended that during the initial visit of all patients presenting with complaints of a pigmented skin neoplasm, the examination area be expanded to assess the condition of the entire skin and visible mucous membranes, including the scalp, nail plates, skin of the feet and hands, and mucous membranes of the oral cavity, genitalia, and conjunctiva, in order to detect other suspicious skin neoplasms [54,57-63].
GPP ALOC 1Grade of Recommendation – A (Level of Evidence – 1) - for adults.
Grade of Recommendation – 3 (Level of Evidence – C) - for children.
Comment: there is significant variation and uncertainty regarding the diagnostic accuracy of visual inspection; the error rate of visual inspection is quite high. Other diagnostic methods must also be used to ensure accurate diagnosis of malignant skin neoplasms. It should also be noted that primary multiple synchronous tumors (melanomas and non-melanoma skin cancers) can be detected in 5–10% of patients [57-61].
Spitzoid lesions (benign and atypical) present the greatest difficulty in the differential diagnosis of melanocytic lesions in children.
Pigmented nevi (Reed nevus) dermoscopically feature a characteristic symmetric structure resembling a "starburst". Such a structure consists of a central dark, homogeneous pigmented structureless area surrounded by peripheral radial lines (pseudopods) or multi-level globules. Non-pigmented Spitz nevi may dermoscopically demonstrate dotted vessels and a negative network (white lines) and present the greatest diagnostic challenge. Sequential digital dermoscopic imaging involves capturing and evaluating sequential dermoscopic images of one or more melanocytic lesions separated by a time interval to detect suspicious changes [64-66].
It is recommended that the examination of a patient complaining of a pigmented skin neoplasm be performed by physicians skilled in the early diagnosis of malignant skin neoplasms (including dermoscopy skills) in order to assess all skin integuments and lymph nodes and detect suspicious lesions [62,67-71].
GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).
It is recommended that epiluminescence microscopy (dermoscopy) of the skin, nail plates, and accessible mucous membrane areas be used during the examination of a patient complaining of a pigmented skin neoplasm, as it increases the accuracy of non-invasive diagnostics and reduces the need for biopsy, though it can only be recommended for use by specialists trained in this method [72-74].
GPP ALOC 1Grade of Recommendation – A (Level of Evidence – 1) - for adults.
Grade of Recommendation – 5 (Level of Evidence – C) - for children.
Comment: signs specific to superficial spreading melanoma include atypical pigment network, regression areas, irregularly shaped dots and globules, streaks, and polychromasia distributed asymmetrically. Additional criteria, such as white-blue structures and polymorphic vessels, are frequently found in invasive melanoma [75-78].
Amelanotic melanoma can present diagnostic challenges. It is typically characterized by a polymorphic vascular pattern, or the diagnosis is made by exclusion in the absence of typical melanocytic and non-melanocytic dermoscopic features [79,80].
Lentigo maligna is characterized by the presence of rhomboidal structures, a pseudonetwork, dotted blood vessels, gray circles, and incomplete follicles [81,82].
Distinctive dermoscopic features of invasive acral melanoma include a parallel ridge pattern and diffuse irregular pigmentation [83-85].
It is recommended to use sequential (digital) monitoring dermoscopy for the primary diagnosis of melanoma in patients with suspected skin malignancy who lack specific dermoscopic criteria for malignancy [74,86-89].
GPP ALOC 1Grade of Recommendation – A (Level of Evidence – 1) - for adults.
Recommendation grade – 4 (evidence level – C) - for children.
Comment: sequential digital dermoscopic imaging involves capturing and evaluating sequential dermoscopic images of one or more melanocytic lesions separated by a time interval to detect suspicious changes. Short-term digital monitoring (within 1.5–4.5 months) can be performed to monitor suspicious melanocytic neoplasms, alongside long-term monitoring for surveillance (usually at intervals of 6–12 months). Long-term digital monitoring is typically used for high-risk patients, generally those with multiple atypical nevi [86-88,90-93]. Digital monitoring dermoscopy can be very useful in children with Spitz nevi that are difficult to distinguish from amelanotic melanoma. For instance, according to Argenziano et al., 80% of Spitz nevi (51/64) underwent complete regression over 25 months; this process was independent of sex, age, and lesion location [94]. Total-body photography can be useful for the early detection of cutaneous melanoma in patients at high risk of developing cutaneous melanoma (e.g., patients with dysplastic nevus syndrome, familial atypical multiple mole melanoma [FAMMM] syndrome, etc.) [95-98].
It is recommended to include an assessment of regional lymph nodes in the physical examination of patients with suspected skin malignancy in order to rule out metastatic involvement of regional lymph nodes [54,62,99].
ROB BLOE 1Recommendation grade – B (evidence level – 1).
Comment: it should be noted that palpation of lymph nodes in patients does not rule out the need for lymph node ultrasound in patients with a confirmed diagnosis, as physical examination of lymph nodes lacks sufficient accuracy.
It is recommended to decide on the feasibility of invasive diagnostics (biopsy) of the neoplasm during the patient appointment based on the analysis of complaints, anamnesis, and physical examination data in order to achieve morphological verification of the diagnosis and formulate a further examination and treatment plan [100-107] (see Appendix B, Fig. 1).
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
2.3 Laboratory Diagnostics
It is not recommended to perform laboratory diagnostic tests in patients prior to morphological confirmation of the diagnosis, unless intercurrent pathology or the patient's general condition requires it for the safe performance of a biopsy, since the diagnosis is established based on the results of other diagnostic methods (see subsections 2.4 and 2.5), while laboratory diagnostics affect prognosis only in patients with an already established diagnosis [54,108-114].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: an elevated neutrophil-to-lymphocyte ratio, as well as a high lactate dehydrogenase level, may be predictors of a poor prognosis in patients with stage III-IV melanoma, but it is specifically the lactate dehydrogenase level that is a required criterion for staging in patients with metastatic melanoma [35,115,116].
Upon diagnosis confirmation, in preparation for the next stage of treatment, it is recommended to perform a general clinical and general biochemical blood test (specifically, determining blood lactate dehydrogenase levels and the neutrophil-to-lymphocyte ratio) to assess melanoma prognosis [114-121] (see also Table 7).
GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).
Comment: additionally, as part of selecting the optimal treatment algorithm for a patient with an established diagnosis, laboratory testing is required to an extent that allows identifying risks of an unfavorable treatment response and contraindications to various types of therapy.
2.4 Instrumental Diagnostics
It is recommended, in the presence of appropriate indications (symptoms of metastasis), to perform comprehensive diagnostic imaging procedures (including radiology) regardless of the stage of the disease for the timely detection of melanoma metastases [54].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended, after establishing the diagnosis in the absence of any complaints and symptoms, to perform diagnostic studies of varying scope to detect occult metastases depending on the stage of the disease (established according to clinical examination and pathomorphological examination of biopsy or surgical material), reflecting the risk of detecting regional and distant metastases, summarized in Table 7 [122–128].
GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).
It is not recommended to perform instrumental diagnostics prior to the morphological confirmation of the diagnosis, unless intercurrent pathology or the patient's general condition requires it for the safe performance of a biopsy [54].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: the treatment and examination plan should not be formulated until the results of the pathomorphological examination are received.
It is recommended to perform an ultrasound examination (hereinafter referred to as US) of regional lymph nodes in patients with stage 0–IV after establishing the diagnosis in order to detect lymph node metastases [99, 128].
GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).
It is recommended, in order to assess the extent of the tumor process in patients with clinical stage IIA–IV after establishing the diagnosis, to evaluate the condition of the chest, abdominal cavity, and pelvic organs by performing computed tomography (hereinafter referred to as CT) of the chest, abdomen, and pelvis. Intravenous contrast enhancement should be performed in all cases unless contraindications to the administration of iodine-containing contrast agents are identified — in this case, CT with IV contrast may be replaced by MRI with IV contrast. An alternative may be positron emission tomography combined with computed tomography (hereinafter referred to as PET/CT) using fluorodeoxyglucose [18F] in "whole-body" mode [126, 128–132].
LeR AQoE 1Level of Evidence — A (Quality of Evidence — 1) — for adults.
LeR CQoE 5Level of Evidence — C (Quality of Evidence — 5) — for children.
Comment: if the optimal diagnostic imaging modality cannot be performed within 4 weeks after diagnosis, chest CT may be replaced by standard chest radiography in two projections, and contrast-enhanced CT of the abdomen and pelvis by ultrasound of the abdominal and pelvic organs [133].
It is recommended to perform magnetic resonance imaging (MRI) of the brain with contrast enhancement:
in patients with stage IIB–IV melanoma for the screening of asymptomatic brain metastases,
in patients with neurological symptoms regardless of the stage of the disease,
in patients with melanoma brain metastases following local and systemic treatment to evaluate treatment efficacy [128, 134–140].
LeR AQoE 1Level of Evidence — A (Quality of Evidence — 1) — for adults.
LeR BQoE 2Level of Evidence — B (Quality of Evidence — 2) — for children.
Comments: Brain MRI is recommended to be performed in the following protocols: before intravenous contrast administration in T1-weighted axial imaging (slice thickness 1–1.5 mm), T2, DWI, FLAIR (slice thickness 3–5 mm). After intravenous contrast administration: T1 in axial projection (slice thickness 1–1.5 mm), 3D T1 high-resolution weighted images in the axial ( or sagittal) plane covering the entire head using isotropic voxel technology (1 mm × 1 mm × 1 mm). Contrast-enhanced computed tomography (CT) for the diagnosis of brain metastases is only possible if there are contraindications to magnetic resonance imaging.
It is recommended that all patients with melanoma of the anal canal or rectum undergo sigmoidoscopy and biopsy to accurately measure the distance from the anocutaneous line to the lower pole of the tumor and obtain material for histological examination [141,142].
GCR CLEL 3Grade of Recommendation – C (Level of Evidence – 3) - for adults.
LeR CQoE 5Level of Evidence — C (Quality of Evidence — 5) — for children.
Comment: accurate determination of the localization of the lower pole of the tumor is necessary when planning surgical treatment, especially when deciding on the feasibility of a sphincter-sparing surgery in patients with rectal melanoma. A biopsy is necessary for the differential diagnosis of melanoma and rectal carcinoma. The macroscopic appearance of the tumor is insufficient for diagnosis. Up to 30% of cases of melanoma of the anal canal and rectum present as amelanotic melanomas, which can be macroscopically interpreted as polyps or internal hemorrhoids [143].
It is recommended that after establishing the diagnosis, all adult patients with anorectal localization of melanoma undergo colonoscopy to assess the extent of mucosal tumor involvement with a biopsy of lesions suspicious for melanoma [144].
GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4).
It is recommended to perform a pelvic MRI in all patients with melanoma of the anal canal or rectum prior to determining treatment strategy in order to assess disease extent [141].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: Pelvic MRI allows determining the location, extent, and depth of tumor invasion, as well as assessing the status of regional lymph nodes. Despite the lack of studies on the role of pelvic MRI in the diagnosis of melanoma of the anal canal and rectum, the principles of surgical treatment planning are similar to those for rectal cancer, which has allowed extrapolating the indications for this diagnostic method [145-148].
It is recommended to include the following information in the pelvic MRI conclusion report for all patients with melanoma of the anal canal or rectum for optimal treatment planning: tumor size, depth of invasion into the rectal wall, minimum distance from the tumor edge to the mesorectal fascia, number and size of pararectal lymph nodes, presence of MRI signs of their malignant involvement, presence of mesorectal fascia involvement by potentially affected lymph nodes, presence of venous invasion, number and size of extrafascial lymph nodes, presence of MRI signs of their malignant involvement; for lower rectal cancer – presence of invasion of the internal sphincter/intersphincteric space/external sphincter/levator ani muscles [141,149].
GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4) - for adults.
GCR CLEL 5Grade of Recommendation – C (Level of Evidence – 5) - for children.
Comment: modern MRI protocols using diffusion-weighted imaging can improve the diagnostic value of the study. Intravenous contrast enhancement does not improve the accuracy of tumor spread assessment [150]. The final decision on the treatment strategy for patients with rectal cancer can only be made based on the results of the MRI examination.
It is recommended that after establishing the diagnosis, patients undergo ultrasound- or CT-guided biopsy of metastatic lesions when metastases are suspected on CT or MRI, in cases where their confirmation fundamentally changes the treatment strategy, in order to obtain morphological confirmation of the metastatic process [54].
GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).
It is recommended that pediatric patients undergo sedation, general anesthesia, or alternative techniques (such as "feed-and-sleep", play therapy, etc.) to obtain high-quality diagnostically significant images during MRI, CT, PET-CT, or other instrumental diagnostic procedures [151-156].
GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).
2.5 Other Procedures
It is recommended to use an excisional biopsy of a suspicious pigmented lesion with a margin of no more than 5 mm (an acceptable margin of 1–3 mm [0.1–0.3 cm]) as a first step to confirm the diagnosis and develop a further examination and treatment plan [8,157-159].
CGR BLEL 1Level of recommendation grade – B (level of evidence – 1).
Comment: excisional biopsy is the recommended standard for establishing the diagnosis of cutaneous melanoma. However, in a number of clinical situations (e.g., a large patch of lentigo on the face requiring differential diagnosis with lentigo maligna melanoma, giant congenital nevi with areas suspicious for malignant transformation, etc.), performing an excisional biopsy of the entire pigmented neoplasm is associated with significant difficulties and unjustified surgical trauma for the patient. In such cases, it is safe to perform a full-thickness incisional (or punch) biopsy. According to a systematic review of 9 studies, including randomized controlled trials, performing an incisional biopsy of melanoma does not negatively affect the prognosis [157].
It should also be borne in mind that cutaneous melanoma is an extremely rare disease in children. A recent analysis of over 20,000 melanocytic neoplasms excised in Italian children and adolescents over a 20-year period showed that 87% of the 38 melanomas occurred at 15–19 years of age, with no cases of melanoma in children under 10 years of age [40], and 594 benign neoplasms are excised to diagnose 1 melanoma in a child under 18 years of age [160]. In this regard, careful follow-up monitoring of a suspicious neoplasm may be the best strategy in children [161].
It is recommended to orient skin incisions during excisional biopsy toward the nearest lymphatic drainage basin, parallel to the cutaneous lymphatic vessels (rather than along skin tension lines or natural skin folds) so that re-excision of the scar (if required) can be performed without difficulty [54,100-107].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: excisional biopsy of a suspicious flat pigmented skin lesion can be safely performed using local infiltration anesthesia. At the same time, it is recommended to avoid trauma to the removed neoplasm prior to its excision [8,100,101,103-106].
It is recommended to perform a pathomorphological examination of the surgical specimen, and the report should reflect the following characteristics to determine the stage of the disease and prognosis [162-172]:
Mandatory characteristics:
determination of the maximum tumor thickness in millimeters according to Breslow;
determination of the Clark level of invasion;
indication of the presence or absence of ulceration of the primary tumor;
determination of the mitotic rate (number of mitoses per 1 mm2) for tumor thickness up to 1 mm inclusive;
assessment of the peripheral and deep resection margins for the presence of tumor cells;
presence of in-transit or satellite metastases.
Additional characteristics:
tumor localization;
presence or absence of spontaneous regression;
neurotropism;
lymphoid infiltration;
histological subtype;
angiolymphatic invasion.
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
It is recommended to perform molecular genetic testing for BRAF gene mutations (exon 15) in biopsy material (or previously excised lymph nodes, or the primary tumor, provided the material meets laboratory requirements for reliable detection or exclusion of molecular genetic alterations) in cutaneous melanoma patients with diagnosed or suspected regional and distant melanoma metastases, as well as in melanoma metastases of unknown primary site; this may influence the choice of a targeted agent (protein kinase inhibitor) in the treatment of the metastatic process [54,173-184].
GRC ALOE 1Level of Evidence – A (Level of Certainty of Evidence – 1) - adults.
GRC ALOE 2Level of Evidence – A (Level of Certainty of Evidence – 2) - children.
It is recommended to perform molecular genetic testing for NRAS (exon 3) and KIT (exons 8, 9, 11, 13, 14, 17, 18) gene mutations in biopsy (surgical) material, or perform comprehensive molecular testing, in cutaneous melanoma patients without a BRAF gene mutation, if distant melanoma metastases are diagnosed or suspected and this may influence the choice of targeted therapy regimens (specifically, the prescription of protein kinase inhibitors or monoclonal antibodies) in the treatment of the metastatic process [185-200].
GRC CLOE 4Level of Evidence – C (Level of Certainty of Evidence – 4) - adults.
GRC CLOE 5Level of Evidence – C (Level of Certainty of Evidence – 5) - children.
It is recommended in mucosal melanoma, if distant melanoma metastases are diagnosed or suspected, to perform molecular genetic testing for KIT gene mutations in biopsy (surgical) material (exons 8, 9, 11, 13, 14, 17, 18) — this may influence the choice of a targeted agent (protein kinase inhibitor) in the treatment of the metastatic process [185-198] [197,201-203]; in the absence of a KIT gene mutation, it is recommended to perform molecular genetic testing for BRAF gene mutations (exon 15) in the biopsy material.
GRC CLOE 4Level of Evidence – C (Level of Certainty of Evidence – 4) - adults.
GRC CLOE 5Level of Evidence – C (Level of Certainty of Evidence – 5) - children.
In children over 12 years of age, it is recommended to perform an excisional biopsy of skin neoplasms when Spitz nevus is suspected, for differential diagnosis with juvenile cutaneous melanoma [161].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: suspicion should be raised by amelanotic papulonodular lesions, size greater than 8–10 mm, and rapid growth. In the presence of lesion asymmetry or surface ulceration, it is advisable to perform an excisional biopsy in patients of any age [161].
It is recommended that all cases of cutaneous melanoma in children under 18 years of age be referred for an in-person or telemedicine consultation to obtain a second opinion on the pathohistological diagnosis at a reference center [44-46].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
It is recommended to perform molecular genetic testing for BRAF gene mutations in biopsy (surgical) material and molecular genetic testing for NRAS gene mutations in biopsy (surgical) material in patients with cutaneous and mucosal melanoma when regional and/or distant melanoma metastases are detected; in the absence of these mutations, it is recommended to perform comprehensive genomic profiling for mutations and translocations in proto-oncogenes using high-throughput sequencing (NGS) when such analysis can influence the choice of drug therapy [175-177,179-183,190,204-226].
GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).
It is recommended for patients with cutaneous and mucosal melanocytic tumors: when the malignant or benign nature of the neoplasm cannot be definitively determined based on histological examination results from an expert-level laboratory, to perform molecular genetic testing for "modifier" molecular alterations in biopsy or surgical material (if the material meets the laboratory requirements for reliable determination of the presence or absence of molecular genetic alterations) — this may help clarify the histological picture. Molecular genetic testing should expediently begin with testing for CDKN2A gene deletion and RREB1 gene amplification; in the absence of these alterations, it is recommended to perform comprehensive genomic profiling for copy number alterations of proto-oncogenes and tumor suppressor genes using multiplex ligation-dependent probe amplification (MLPA) or high-throughput sequencing (NGS) [227-229].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
It is recommended to perform molecular genetic testing for mutations in the promoter region of the TERT gene in biopsy or surgical material (if the material meets the laboratory requirements for reliable determination of the presence or absence of molecular genetic alterations) in patients with a confirmed diagnosis of Spitzoid melanoma — this may help identify tumors with a high and very high risk of metastasis [230].
GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).
It is recommended, when a hereditary nature of the disease is suspected (multiple primary malignancies and/or a burdened family oncological history), to recommend a consultation with a geneticist followed by molecular genetic testing to rule out or confirm any tumor predisposition syndrome [231].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
It is recommended to consider surgical intervention as the primary method of radical treatment for patients with stage 0–III cutaneous melanoma [54,158,173,232-248].
ROB BLOE 1Recommendation grade – B (evidence level – 1).
Comment: adjuvant therapy is additionally administered according to indications (see section 3.3).
3.1. Treatment of localized stages of the disease (I–II)
It is recommended to perform radical excision of the primary tumor within healthy tissue as the core stage of treatment for local cutaneous melanoma in patients with stage I–II disease [158,159,235-237,239,241,243,249,250].
GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).
The choice of surgical margin is based on the results of pathomorphological examination of the biopsy (surgical) material, specifically the tumor thickness. Currently, to improve long-term treatment outcomes and prevent tumor recurrence in already established stages, it is recommended to use the following margins [158,159,235-237,239,241,243,249,250]:
0.5 cm for melanoma in situ;
1 cm for a Breslow tumor thickness of ≤ 2 mm;
2 cm for a tumor thickness of > 2 mm.
GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).
Comment: modified resection options with smaller margins are possible to preserve organ function in cutaneous melanoma of the digits or earlobe [245,251-254].
It is recommended to initially perform an excisional biopsy of the pigmented lesion with a margin of no more than 0.5 cm from the visible edge of the pigmented tumor to determine tumor thickness. If the diagnosis of cutaneous melanoma is confirmed, the post-biopsy scar is excised with a wider margin within 4–8 weeks (see also section 2.5) [158,159,235-237,239,241,243,249,250].
GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).
If an excisional biopsy is not performed due to a clinically obvious diagnosis, it is not recommended to expand the margins from the visible tumor edges by more than 2 cm, since without precise knowledge of the microstage, this will lead to unnecessary manipulations related to postoperative wound closure (e.g., various types of complex plastic surgery) [158,159,235-237,239,241,243,249,250].
GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).
If a patient is confirmed to have cutaneous melanoma, it is recommended to excise the post-biopsy scar with a wider margin within 4 to 8 weeks, depending on the histological characteristics of the tumor, in order to prevent melanoma recurrence in the scar area (see section 3.1) [158,159,235-237,239,241,243,249,250].
GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).
If surgical excision of the primary tumor is impossible due to severe comorbidities or the presence of tumor cells at the resection margins after primary tumor removal, and re-excision is not feasible, adult patients are recommended to undergo local radiotherapy in the following fractionation regimens: 64–68 Gy in 32–35 fractions over 6–7 weeks; 50.0–57.5 Gy in 20–23 fractions over 4–5 weeks [255-258].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
In adult patients, routine prophylactic lymphadenectomy or preoperative radiotherapy to either regional lymph nodes or the primary tumor site is not recommended [259-264].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Patients are recommended to undergo sentinel lymph node biopsy when the primary tumor thickness is greater than 0.8 mm according to Breslow in order to correctly stage the disease, determine the prognosis, and identify indications for adjuvant therapy [248,265-281].
GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).
Comment: sentinel lymph node biopsy is performed in specialized centers equipped with appropriate facilities and trained personnel.
The question of performing lymphadenectomy in adult patients if micrometastases are detected in the sentinel lymph node is recommended to be discussed with the patient, weighing the potential risks of such surgery and the expected benefit taking into account the MSLT-II study data [273]. An alternative to immediate lymphadenectomy may be careful monitoring of the regional lymphatic basin using expert-level ultrasound [273].
GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).
During the pathomorphological examination of the surgical specimen, special attention is recommended to be paid to the morphological analysis of the removed sentinel lymph node(s) during sentinel lymph node biopsy: it is strongly recommended to prepare as many sections as possible, and in addition to hematoxylin and eosin staining, to use immunohistochemical staining for melanoma-specific markers (Melan A, tyrosinase, HMB45, or SOX-10). Immunohistochemical staining is recommended to be performed routinely in the absence of signs of metastatic involvement on hematoxylin and eosin staining [282-297].
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
If sentinel lymph node biopsy cannot be performed, it is recommended to examine the regional lymph nodes as thoroughly as possible, using ultrasound to guide fine-needle aspiration of the suspicious lymph node followed by cytological examination [298-302].
GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).
3.1.1 Treatment of localized stages of mucosal melanoma
For mucosal melanoma in adult patients, surgery is recommended to be considered as the primary treatment method for patients with localized disease stages (e.g., T3-4a N0-1 located in the upper respiratory and digestive tracts). For principles of treating more advanced stages, see section 3.4. "Treatment of patients with metastatic and unresectable cutaneous melanoma (IIIC/D unresectable – IV)" [303-309].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
For mucosal melanoma of the nasal cavity and paranasal sinuses at stage T3-4a, N0, adult patients srecommended [sic -> are recommended] to undergo surgery with wide local excision within healthy tissue followed by adjuvant radiotherapy to the primary tumor site in 4–6 weeks with a cumulative dose of 60–70 Gy (in the presence of high-risk pathological recurrence factors), 46–55 Gy to low-risk zones, and 54–63 Gy to intermediate-risk zones [303,304,306,307,309-322].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
For mucosal melanoma of the nasal cavity and paranasal sinuses at stage T3-4a, N1, adult patients are recommended to undergo surgery as the first treatment step, involving removal of the primary tumor and modified radical neck dissection (fascial-compartment excision of neck adipose tissue) on the affected side or bilaterally in case of bilateral involvement. The second treatment step is adjuvant radiotherapy in 4–6 weeks to the primary tumor site with a cumulative dose of 60–70 Gy (in the presence of high-risk pathological recurrence factors), 46–55 Gy to the low-risk area, and 54–63 Gy to the intermediate-risk zones [303,304,306,307,309-322].
GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).
For mucosal melanoma of the oral cavity, oropharynx, hypopharynx, and larynx at stage T3-4a, N0, patients are recommended to undergo surgery as the first step, involving primary tumor removal and ipsilateral prophylactic neck lymph node dissection. The second treatment step is adjuvant radiotherapy in 4–6 weeks to the primary tumor site with a cumulative dose of 60–70 Gy (in the presence of high-risk pathological recurrence factors), 46–55 Gy to the low-risk area, and 54–63 Gy to the intermediate-risk zones [303,304,306,307,309-322].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
For mucosal melanoma of the oral cavity, oropharynx, hypopharynx, and larynx at stage T3-4a, N1, patients are recommended as a first treatment step to undergo surgery consisting of primary tumor removal and ipsilateral modified radical neck dissection (fascial-compartment excision of neck adipose tissue) or bilateral dissection in case of bilateral involvement. The second treatment step is adjuvant radiotherapy in 4–6 weeks to the primary tumor site with a cumulative dose of 60–70 Gy (in the presence of high-risk pathological recurrence factors), 46–55 Gy to the low-risk area, and 54–63 Gy to the intermediate-risk zones [303-316].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
For mucosal melanoma of the head and neck region at stage T4b, N0-1, adult patients are recommended definitive radiotherapy to the primary tumor site and involved regional lymph nodes with a cumulative dose of 66–70 Gy, and 50–63 Gy to zones of low and intermediate recurrence risk [303,304,306,307,309-322].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
Comment: all patients with mucosal melanoma localized in the head and neck region must be evaluated prior to treatment by a surgical oncologist specializing in head and neck tumors, who should take the following steps: review the adequacy of the biopsy material, staging, and tumor imaging (CT, MRI) to determine the extent of the tumor, rule out the presence of a synchronous primary tumor, assess current functional status and the feasibility of potential surgical treatment if the primary treatment was non-surgical, and develop a prospective follow-up plan that will include adequate dental, nutritional, and lifestyle assessments, as well as interventions and any other additional studies required for complete rehabilitation. For patients undergoing elective surgery, the surgical procedure, margins, and reconstruction plan must be designed to resect the clinically apparent tumor with tumor-free surgical margins. Assessment of operability. Involvement of the following structures by the tumor is associated with a poor prognosis or is classified as stage T4b (e.g., unresectability associated with the technical inability to obtain clear resection margins): significant involvement of the pterygopalatine fossa, severe trismus due to tumor infiltration of the pterygoid muscles; macroscopic tumor extension to the skull base (e.g., erosion of the pterygoid plates or sphenoid bone, enlargement of the foramen ovale, etc.); potential invasion (encasement) of the common or internal carotid artery wall. Encasement is usually assessed radiologically (by CT and MRI) and is diagnosed if the tumor surrounds $\ge$ 270\degree of the carotid artery circumference; direct tumor extension from regional lymph nodes with skin involvement, direct extension to mediastinal structures, prevertebral fascia, or cervical vertebrae [303-309].
Excision of the primary lesion. Whenever possible, the primary tumor should be excised en bloc. Surgical excision should be planned based on the extent of the primary tumor established during clinical examination and careful interpretation of relevant radiographs. If the tumor is adjacent to a motor or sensory nerve, perineural invasion cannot be ruled out. In this situation, the nerve should be exposed proximally and distally and resected to obtain a clear resection margin. Frozen section analysis (urgent pathoanatomical examination of biopsy material) of the proximal and distal nerve margins has been confirmed to be useful in obtaining tumor-free tissue. Adequate intervention may require marginal, partial, or sagittal resection of underlying bone structures in tumors involving or adjacent to the periosteum. Bone resection is indicated for massive tumor infiltration of the bone periosteum (determined by tumor fixation to it) or when signs of direct tumor bone invasion are detected intraoperatively or during a complete preoperative evaluation. The extent of surrounding soft tissue and bone resection will depend on the extent of involvement assessed clinically and intraoperatively [303,306,323-330].
Resection margins. Adequate tumor removal in soft tissues is defined as a distance from the resection margin to the macroscopically visible tumor of $\ge$ 2 cm or a negative frozen section margin. In general, frozen section evaluation is usually performed intraoperatively if the macroscopically tumor-free zone at the resection margin is < 2 cm, the resection line cannot be determined due to unclear tumor borders, or residual tumor is suspected. A detailed description of the resection margin must be included in the operative report. Margins can be assessed on the resected specimen or, alternatively, from the properly oriented tumor bed. A clear margin is defined as a distance from the invasive tumor front of $\ge$ 5 mm to the resection margin. A close margin is defined as a distance from the invasive tumor front to the resection margin of < 5 mm. The primary tumor should be marked in such a way that the pathologist can adequately assess the orientation of the specimen. Neck dissection specimens should be oriented or sectioned sequentially to determine the level of lymph nodes included in the dissection zone. Reconstruction of surgical defects should be performed using conventional techniques at the surgeon's discretion. Primary closure is recommended whenever possible, but wide tumor-free resection margins should not be compromised. Plastic closure using local/regional flaps, free flaps, split-thickness skin grafts, or other flaps with/without defect reconstruction is performed at the surgeon's discretion [303,306,309,323-330].
It is recommended that patients with melanoma of the anal canal or rectum, for the purpose of radical removal of the primary tumor, prefer local excision provided there is no evidence of regional lymph node involvement on imaging, the possibility of achieving resection margins greater than 1 mm (R0), and preservation of the function of the rectal sphincter apparatus [141,331-333].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: there is no evidence of improved overall survival when the scope of surgery is expanded to rectal extirpation or intersphincteric/extralevator abdominoperineal resection. Performing extended surgeries is permissible, but only after obtaining written informed consent from the patient stating that there is no reliable evidence of the benefit of such an approach. Achieving an R0 resection significantly improves local disease control and is an important goal of surgical treatment [334].
It is recommended to perform local excision in patients with anal canal or rectal melanoma for palliative removal of the primary tumor, provided that negative resection margins of more than 1 mm (R0) can be achieved and the sphincter function of the rectum is preserved [141,331-333].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: extension of the surgical intervention scope to rectal extirpation or extralevator abdominoperineal resection is possible only in the presence of pronounced symptoms from the primary tumor, such as clinically significant bleeding, intestinal obstruction, or pain syndrome refractory to non-narcotic analgesics.
It is recommended to perform extralevator abdominoperineal resection, rectal extirpation, or low anterior resection of the rectum (depending on the exact tumor location and extent of the tumor process) in adult patients with anal canal or rectal melanoma involving regional lymph nodes for the purpose of radical tumor removal [335].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
Comment: involvement of regional lymph nodes without distant metastasis is relatively rare in patients with rectal and anal canal melanoma. When planning radical surgical treatment, it is advisable to have a second specialist independently review the pelvic MRI to rule out false-positive assessment of regional lymph node involvement. Data on the benefit of regional lymphadenectomy in anal canal melanoma are contradictory. Most authors report no impact of regional lymph node involvement on survival [336-338]. Nevertheless, there are clinical case reports demonstrating long-term survival in patients with mesorectal lymph node involvement following rectal extirpation [335]. Given the lack of high-level evidence, the decision regarding the extent of surgery should be made jointly with the patient, favoring a potentially curative method—extralevator abdominoperineal resection—although the likelihood of achieving long-term survival remains unestablished.
It is recommended to perform a repeat local excision in patients with anal canal or rectal melanoma to achieve local control following local excision if tumor involvement of the resection margin (R1) is detected, provided it is technically feasible and preserves the sphincter function of the rectum [141,331-333].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: if the initial treatment plan was local tumor excision, the detection of tumor cells at the resection margin (R1) is an indication for repeat local excision, but not for changing the overall treatment strategy. Expanding the scope of surgery is advisable only if repeat local excision is technically unfeasible or would result in irreversible impairment of the rectal sphincter function.
It is recommended that patients with melanoma metastases of the anal canal to the inguinal lymph nodes undergo inguinal lymphadenectomy solely for the purpose of controlling potential disease symptoms (tumor bleeding, tumor breakdown, compression of vascular structures) [337].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: there are no data regarding a potential increase in survival after inguinal lymphadenectomy, nor regarding long-term survival following inguinal lymphadenectomy [337].
3.2. Treatment of patients with resectable stage III cutaneous melanoma and stage III equivalents
Patients with stage III cutaneous melanoma represent a heterogeneous group regarding treatment tactics. From a practical standpoint, a distinction should be made between a resectable process and an unresectable locally advanced process (including lymph node conglomerates and/or in-transit or satellite metastases – clinical variants of stage IIIB or IIIC/D). Recommendations for the treatment of patients with unresectable stage IIIC/D cutaneous melanoma are discussed in Section 3.4.
It is recommended to perform an adequate excision of the primary tumor (if not previously performed) (see Section 3.1) to improve long-term treatment outcomes and prevent tumor recurrence [158,159,235-237,239,241,243,249,250].
GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).
It is recommended to perform regional lymphadenectomy in all patients with resectable stage III cutaneous melanoma in the presence of clinically or radiologically detectable metastases in regional lymph nodes to improve long-term treatment outcomes and prevent tumor recurrence [339-342].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
When performing lymphadenectomy in patients with stage III cutaneous melanoma to improve long-term treatment outcomes and prevent tumor recurrence, it is recommended to perform the most complete removal of adipose tissue in the anatomical region whose lymph nodes contain melanoma metastases (e.g., levels Ib–V of the neck adipose tissue (Ia – as indicated), levels I–III of the axillary adipose tissue, superficial and deep inguinal lymph nodes) [339-342].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: in cases of clinically detectable involvement of deep inguinal lymph nodes, major attention should be paid to the external iliac lymph nodes. Some researchers, in cases of massive involvement of deep inguinal lymph nodes (more than 3) or involvement of Cloquet's node (Rosenmüller's node), recommend extending the scope of surgery to include the removal of ipsilateral external iliac lymph nodes, as the frequency of their involvement can reach 20–24% [343].
It is recommended to determine the following parameters during pathomorphological examination of melanoma metastases in regional lymph nodes for correct staging and prognosis determination [54,168,344]:
number of removed lymph nodes;
number of involved lymph nodes;
character of lymph node involvement:
partial involvement (number of lymph nodes);
total involvement (number of lymph nodes);
extracapsular extension (number of lymph nodes).
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended to offer patients, after radical lymphadenectomy and in the absence of contraindications, adjuvant systemic therapy, while informing the patient about the potential benefits and limitations of this treatment method (see Section 3.3) [223,345-352].
GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).
It is recommended to offer adult patients at high risk of regional recurrence after radical lymphadenectomy, in order to reduce the probability of regional recurrence in the absence of contraindications, prophylactic postoperative radiation therapy to the affected lymphatic drainage area, informing the patient about the potential benefits and limitations of this treatment method [353,354].
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
Comment: according to conducted studies, postoperative radiation therapy reduces the risk of regional recurrence in high-risk patients, but does not affect overall survival [354]. High-risk factors for regional recurrence include:
involvement of 1 or more parotid lymph nodes, 2 or more cervical or axillary lymph nodes (or with a lymph node size greater than 3 cm), 3 or more inguinal-femoral lymph nodes (or with their size greater than 4 cm);
extracapsular extension of the metastasis beyond the lymph node capsule [354,355]179].
Adjuvant external beam radiation therapy is administered in the following regimens: 50–66 Gy in 25–33 fractions over 5–7 weeks. (Level of Evidence 4, Grade of Recommendation C) [356]; 48 Gy in 20 fractions over 4 weeks. (Level of Evidence 2, Grade of Recommendation B) [354]. The use of advanced external beam radiation therapy techniques, such as IMRT and VMAT, makes it possible to reduce damage to healthy tissues [357,358].
In the presence of unresectable metastases in regional lymph nodes, palliative radiation therapy to this area may be performed. Various treatment regimens are used, for example: 48 Gy in 20 fractions over 4 weeks [353]; 50 Gy in 20 fractions over 4 weeks [258].
3.3. Recommendations for adjuvant therapy of stage II and III cutaneous melanoma and stage III equivalents
It is recommended to evaluate the risk of progression and death from cutaneous melanoma after radical surgical treatment in order to determine indications for adjuvant therapy. To assess the risk, it is recommended to use the 8th edition of the AJCC/UICC TNM classification, which includes the main prognostic factors (see Subsection 1.5.2 and Section 7) [344,359].
GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).
It is recommended to offer adjuvant drug therapy (Table 10) to patients with high and intermediate risk of progression after radical surgical treatment (i.e., patients with stages IIB–III) in the absence of contraindications, informing the patient about the potential benefits and limitations of this treatment method [54,223,345-348,350-352,360-363].
GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).
Table 10. Recommended adjuvant therapy regimens for cutaneous melanoma by disease stage in adults3
Stage | Presence of V600 mutation in the BRAF gene | Optimal regimens | Alternative regimens when optimal ones are unavailable |
|---|---|---|---|
IIB, IIC | Regardless of status |
| #Interferon alfa-2b 3 million IU or 5 million IU s.c. 3 times/week for 12 months [361,364-366] |
IIIA | BRAF V600 mut |
OR
OR
|
OR
|
IIIA | BRAF V600 wild type |
OR
| |
IIIB, IIIC/D | BRAF V600 mut |
OR
OR
OR
OR
OR
| #Interferon alfa-2b 3 million IU or 5 million IU 3 times/week for 24 months [364] [347,361,366] |
IIIB, IIIC/D | BRAF V600 wild type |
OR
OR
OR
OR
| #Interferon alfa-2b 3 million IU or 5 million IU 3 times/week for 12 months [364] [347,361,366] |
3Patients in all groups should be offered participation in clinical trials if available.
Note. BRAF V600 mut – an activating mutation in the BRAF gene at position 600 of exon 15 resulting in the substitution of the nucleotide encoding valine for another amino acid (most commonly a nucleotide encoding glutamic acid). BRAF V600 wild type – wild type (absence of V600 activating mutations) of the BRAF gene.
Comment: adjuvant therapy with #interferon alfa-2b shows benefits only in patients with ulcerated primary cutaneous melanoma. The prescription of #interferon alfa-2b in the adjuvant setting in patients with non-ulcerated primary tumors is not recommended. Adjuvant therapy with PD-1 blocking monoclonal antibodies is being studied for patients with IIB-IIC stage, demonstrating an effect on progression-free survival, although its effect on overall survival is not yet available [363,370,371]. In patients with stage IIIA equivalent, the magnitude of benefit from such therapy is low, and careful active surveillance can serve as an alternative for this patient population [223,351].
For adult patients who have undergone radical surgery for distant metastases of cutaneous melanoma, it is recommended to administer adjuvant treatment using monoclonal antibodies (hereinafter referred to as MAbs) that block the interaction between the programmed death receptor (PD-1) and its ligands (hereinafter referred to as PD-1 blocking MAbs) (nivolumab**). In case of contraindications, active surveillance or participation in clinical trials (if available) may be an alternative [54,346-348,350,352,360-362].
CGR BLEL 1Level of recommendation grade – B (level of evidence – 1).
It is not recommended to administer adjuvant therapy to cutaneous melanoma patients with a favorable prognosis and low risk of disease progression (stages IA, IB, IIA) [364,372].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is not recommended to administer adjuvant therapy with interferon alfa-2a and interferon alfa-2b to patients with cutaneous melanoma in whom the risks associated with adverse events during adjuvant therapy outweigh the expected benefit [360,361,373-375].
CGR BLEL 1Level of recommendation grade – B (level of evidence – 1).
Comment: given that immunotherapy with interferon alfa-2a or interferon alfa-2b is associated with well-known risks of adverse events, it is necessary to identify a group of patients for whom this treatment is contraindicated. After analyzing the literature data, experts concluded that the risk outweighs the benefit of prescribing therapy with interferon alfa-2a and interferon alfa-2b in the following cases (but not limited to them) [360,373-375]:
mental disorders, including severe depression;
liver cirrhosis of any etiology;
autoimmune diseases;
severe organ dysfunction (cardiac, hepatic, renal, etc.) (grade III–IV according to CTCAE v. 3.0 [376]);
pregnancy or planned pregnancy;
psoriasis;
patient's inability to adequately follow medical prescriptions.
Therefore, experts recommend ruling out the listed contraindications in patients before prescribing adjuvant immunotherapy with #interferon alfa-2b, resorting to consultations with specialists (general practitioner, psychiatrist, dermatovenereologist, etc.) if necessary. Contraindications to the drug specified by the manufacturer in the instructions for use should also be taken into account.
It is recommended to initiate adjuvant immunotherapy in patients no later than 3 months after surgical treatment, following complete healing of the postoperative wound. It is not recommended to start adjuvant treatment if more than 3 months have passed since surgery, as the efficacy of adjuvant therapy initiated at later dates has not been studied [223,351,352,361].
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
Randomized trials have not demonstrated any advantages of intermittent regimens of #interferon alfa-2b, therefore they are not recommended for use in routine practice [373,377].
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
It is not recommended to use chemotherapy in routine practice for the adjuvant treatment of adult patients with cutaneous melanoma [378-385].
GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).
Comment: according to numerous international studies, the use of chemotherapy in the adjuvant setting after radical treatment of stage IIB–III cutaneous melanoma provides no clinical benefit and may reduce overall survival.
It is not recommended to use immunostimulants (ATX group - L03AX Other immunostimulants) or other interferons (including interferon gamma**) [386], except for #interferon alfa-2b in the adjuvant setting for cutaneous melanoma [361,364,365].
LoR CLE 2Level of Recommendation – C (Level of Evidence – 2).
Comment: available clinical trial data indicate a lack of efficacy of interferon gamma** in the adjuvant setting; regarding other drugs, available scientific data are insufficient for their safe use [54].
For cutaneous melanoma with a high risk of progression in individuals under 18 years of age, it is recommended to administer adjuvant therapy with #pembrolizumab** 2 mg/kg every 21 days IV infusion (30 minutes) for 12 months, informing the patient (and/or their parents, legal representatives) about the potential benefits and limitations of this treatment method by decision of a medical board [387,388].
GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).
Comment: adjuvant therapy for cutaneous melanoma in pediatric patients has been insufficiently studied: due to the rarity of this disease in children, large randomized trials of modern antineoplastic drugs in this patient category have not been conducted. The Working Group for the development and revision of clinical guidelines recommends the participation of patients under 18 years of age in clinical trials. To date, #interferon alfa-2b in various regimens [347,348,389-391] (for recommended interferon regimens, see Table 10. "Recommended regimens of adjuvant therapy for cutaneous melanoma depending on the stage of the disease in adults") and #pembrolizumab [388] have been studied in pediatric practice as adjuvant therapy. The prescription of other adjuvant therapy (in accordance with recommendations for adult patients) is possible by a medical concilium for life-saving indications.
3.3.1 Recommendations for neoadjuvant therapy of stage III cutaneous melanoma and stage III equivalents
Introduction: data from recent studies demonstrate very encouraging results with neoadjuvant immunotherapy in patients with melanoma involving regional lymph nodes. Apparently, this strategy has an advantage over the standard approach. Soon, the extent of surgical interventions for stage IIIB-D melanoma equivalents is also likely to be revised toward reducing invasiveness and the volume of removed tissue (removal of sentinel nodes instead of complete lymph node dissection). However, to date, we do not have sufficient data to recommend reducing the scope of surgery, yet there is sufficient data to recommend the neoadjuvant approach for patients with resectable melanoma metastases [392-397].
It is recommended that adult patients with regional lymph node involvement (stage IIIB-D disease or equivalent) undergo preoperative immunotherapy followed by regional lymphadenectomy and subsequent adjuvant therapy (with neoadjuvant therapy – for a total duration of up to 12 months) [398] [399]. The regimens are provided in the table below (Table 11).
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
Table 11. Neoadjuvant therapy regimens.
Drug | Dose | Route of administration | Days of administration/intake | Cycle duration | |
|---|---|---|---|---|---|
Combined immunotherapy aCTLA4 + aPD1 [398] (preferred regimen) | Ipilimumab** | 80 mg | IV infusion | every 21 days | Followed by complete regional lymphadenectomy and, if applicable, resection of in-transit metastases at week 6. Patients with a complete or near-complete pathological response to treatment (≤ 10% residual viable tumor) receive no adjuvant therapy (observation only), whereas patients with a partial pathological response (11% to 50% residual viable tumor) or no response (> 50% residual viable tumor) subsequently receive adjuvant therapy with dabrafenib** (at a dose of 150 mg twice daily) and trametinib** (at a dose of 2 mg once daily) for 46 weeks (in the presence of a BRAF V600E or V600K mutation), or receive an additional 11 cycles of adjuvant nivolumab** therapy (at a dose of 480 mg) every 4 weeks (in the absence of a BRAF mutation). |
Nivolumab** | 240 mg | IV infusion | |||
aPD1 monotherapy [399] | Pembrolizumab** | 200 mg | IV infusion | once every 21 days, | up to 2 months (3 administrations) prior to lymphadenectomy, followed by continuation for a total of up to 12 months of therapy |
It is recommended that patients receiving preoperative (neoadjuvant) immunotherapy with regional lymph node involvement (stage IIIB-D disease or equivalent) undergo evaluation of pathological response after regional lymphadenectomy [396,398-402].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
It is recommended that patients with disease progression during preoperative (neoadjuvant) immunotherapy with regional lymph node involvement (stage IIIB-D disease or equivalent) and the presence of a BRAF gene mutation be switched to adjuvant combination therapy with BRAF and MEK inhibitors [398] [403] (Table 11).
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
3.4. Treatment of patients with metastatic and unresectable cutaneous melanoma (stage IIIC/D unresectable – IV or equivalent)
3.4.1. General principles for first-line therapy selection in patients with metastatic or unresectable cutaneous melanoma
It is recommended that an adult patient's condition be assessed using the WHO/ECOG performance status scale (see Appendix G1), along with evaluation of comorbidities and life expectancy to determine the optimal management strategy [404,405].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
It is recommended that when selecting first-line therapy for all patients with metastatic or unresectable melanoma, molecular genetic testing of the tumor for mutations in exon 15 of the BRAF gene be performed (if not done previously). Archival tumor tissue or fresh tissue obtained via biopsy (open, core-needle biopsy, etc.) may be used for testing if it will influence the choice of subsequent management strategy [54,173-184].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
In the absence of a mutation in the BRAF gene ("wild-type"), it is recommended that all patients with metastatic or unresectable melanoma undergo molecular genetic testing for mutations in the NRAS gene (exon 3) and KIT gene (exons 8, 9, 11, 13, 14, 17, 18) in the biopsy (surgical) material when choosing 1st-line therapy, or undergo comprehensive molecular testing if distant melanoma metastases are diagnosed or suspected and this may influence the choice of targeted therapy regimens (specifically, the administration of protein kinase inhibitors or monoclonal antibodies) in the treatment of the metastatic process [185-200].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
Comment: there is also evidence that the KIT protein kinase inhibitor may be effective in the presence of mutations in exons 8 and 18 of the KIT gene [197,201-203].
If it is not possible to perform molecular genetic testing of the tumor for the presence of a mutation in the BRAF gene (or KIT) within 4 weeks after establishing the diagnosis of metastatic melanoma (lack of material for analysis, absence of appropriate equipment at the facility, etc.) in the absence of other contraindications, it is recommended to initiate antitumor therapy for the patient in accordance with subsection 3.4.4 of these guidelines [406,407].
GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).
It is recommended to give preference to combination immunotherapy with CTLA-4 blocking monoclonal antibodies and PD-1 blocking monoclonal antibodies for patients with a BRAF gene mutation (in the absence of clinically significant symptoms, low tumor burden, low rate of disease progression, and clinically significant immune system disorders), and/or with asymptomatic brain metastases (regardless of the molecular status of the tumor), and/or in mucosal melanoma (regardless of the tumor molecular status prior to monotherapy with PD-1 blocking monoclonal antibodies or combined treatment with BRAF and MEK inhibitors [408-413].
GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).
3.4.2. Choice of 1st-line therapy in adult patients with metastatic or unresectable cutaneous melanoma with a BRAF gene mutation
In patients with a BRAF gene mutation, it is recommended to use combined treatment with PD-1 blocking monoclonal antibodies and CTLA-4 blocking monoclonal antibodies, or a combination of BRAF and MEK protein kinase inhibitors (hereinafter referred to as PKIs), or monotherapy with PD-1 blocking monoclonal antibodies in the 1st line of therapy. If combined treatment with BRAF and MEK PKIs or PD-1 blocking monoclonal antibodies is unavailable, monotherapy with BRAF PKIs is possible [180,181,408,414-420]. Treatment with BRAF and MEK PKIs is carried out until disease progression or the development of severe unmanageable toxicities. Regimens of administration are given below (Table 12 and Table 13).
GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).
In patients with high tumor burden and a high rate of disease progression and/or clinically pronounced symptoms, it is recommended to give preference to the combination of BRAF and MEK PKIs. In patients with metastatic melanoma who have no symptoms of the disease and no activating mutation in the BRAF gene, monotherapy with PD-1 blocking monoclonal antibodies should be considered the preferred treatment option, whereas in patients without symptoms of the disease and without an activating mutation in the BRAF gene, combination therapy with PD-1 blocking monoclonal antibodies and CTLA-4 blocking monoclonal antibodies should be considered the preferred treatment option [413].
GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).
Table 12. Administration regimens of BRAF and MEK PKIs in adult patients (for all administration regimens LEL 2, GRP A).
Therapy regimen | Drug | Dose | Route of administration | Administration days | Cycle duration, days, schedule |
|---|---|---|---|---|---|
Combination therapy [215,216,421,422] | Encorafenib | 450 mg once daily | orally | daily | prolonged |
Binimetinib | 45 mg twice daily | orally | daily | prolonged | |
Combination therapy [218,423,424] | Vemurafenib** | 960 mg twice daily | orally | daily | prolonged |
Cobimetinib** | 60 mg once daily | orally | days 1 to 21, 7 days off | prolonged | |
Combination therapy [175,425,426] | Dabrafenib** | 150 mg twice daily | orally | daily | prolonged |
Trametinib** | 2 mg once daily | orally | daily | prolonged | |
Monotherapy [424,427] | Vemurafenib** | 960 mg twice daily | orally | daily | prolonged |
Monotherapy [428] | Dabrafenib** | 150 mg twice daily | orally | daily | prolonged |
Monotherapy [215,216,421,422] | #Encorafenib | 300 mg once daily | orally | daily | prolonged |
It is not recommended to administer BRAF inhibitors or a combination of BRAF and MEK inhibitors to patients with an unknown tumor BRAF mutation status, as there is evidence of potential paradoxical activation of the MAPK signaling pathway and accelerated tumor growth when BRAF inhibitors are used in cell lines lacking the BRAF mutation [406,407].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Considering the specific profile of dermatological adverse events associated with BRAF and MEK inhibitors, in particular the risk of cutaneous squamous cell carcinoma and other skin tumors, it is recommended to regularly perform physical examinations of the patient's skin during treatment [176,219,429].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
Comment: if squamous cell carcinoma or keratoacanthoma is suspected, surgical removal followed by pathomorphological examination of the biopsy or surgical specimen is required; meanwhile, therapy with BRAF inhibitors or a combination of BRAF and MEK inhibitors may be continued without treatment interruption and/or dose reduction [221,427].
When administering BRAF inhibitors or a combination of BRAF and MEK inhibitors, treatment efficacy is recommended to be evaluated every ~8 weeks, avoiding treatment breaks during the efficacy assessment period. To assess treatment efficacy, it is recommended to evaluate the patient's general condition using diagnostic imaging methods (see Table 9, Section 2.4), as well as standard criteria for response to cytotoxic therapy (RECIST 1.1, Appendix G3) [180,430,431].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
If there are signs of disease progression during therapy with BRAF inhibitors or a combination of BRAF and MEK inhibitors, or if signs of intolerance to such therapy appear while maintaining a satisfactory general condition of the patient (ECOG 0–2) and an expected life expectancy of more than 3 months, it is recommended to switch the adult patient to PD-1 monoclonal antibody blockade therapy or a combination of PD-1 and CTLA-4 monoclonal antibody blockade [408,414-418,432]. Regimens are provided below (Table 13).
GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).
Comment: PD-1 monoclonal antibody monotherapy and combination therapy with PD-1 and CTLA-4 monoclonal antibodies demonstrate similar outcomes in patients with melanoma resistant to BRAF and MEK inhibitors. However, combination therapy with PD-1 and CTLA-4 monoclonal antibodies was associated with a higher incidence of adverse events compared to monotherapy [433].
Table 13. Administration regimens of PD-1 and CTLA-4 monoclonal antibodies in adult patients.
Therapy regimen | Drug | Dose | Route of administration | Administration days | Cycle duration, days, schedule |
|---|---|---|---|---|---|
Monotherapy [414-416] | Nivolumab** | 3 mg/kg OR | IV infusion 30–60 min. | every 14 days | Continuously |
240 mg [434] OR | IV infusion | every 14 days | Continuously | ||
480 mg [369] | IV infusion | Once every 28 days | Continuously | ||
Monotherapy [416-418] | Pembrolizumab** | 200 mg OR | IV infusion 30 min. | every 21 days | Continuously |
Pembrolizumab** | 400 mg [367] | IV infusion 30 min. | Once every 42 days | Continuously | |
Monotherapy [435,436] | Prolgolimab** | 1 mg/kg | IV infusion 30–60 min. | every 14 days | Continuously (LEL 2, GOR B) |
Combination therapy with CTLA-4 and PD-1 monoclonal antibodies (IPI 3 / NIVO 1) [408,409,414,437] | Nivolumab** (on the same day as ipilimumab**) | 1 mg/kg | IV infusion 30 min. | every 21 days | Total of no more than 4 administrations |
Ipilimumab** (on the same day as nivolumab**) | 3 mg/kg | IV infusion over 30 minutes | every 21 days | Total of no more than 4 administrations | |
Maintenance phase: nivolumab** | 3 mg/kg OR | IV infusion | every 14 days | Continuously | |
240 mg OR | IV infusion | every 14 days | Continuously | ||
480 mg IV | IV infusion | Once every 28 days | Continuously | ||
Combination therapy with CTLA-4 mAb and PD-1 mAb (IPI 1 / NIVO 3) [437] (Level of recommendation – B) (level of evidence – 4). | Nivolumab** (on the same day as ipilimumab**) | 3 mg/kg | IV infusion 30 min. | every 21 days | Total of no more than 4 administrations |
Ipilimumab** (on the same day as nivolumab**) | 1 mg/kg | IV infusion 30 min. | every 21 days | Total of no more than 4 administrations | |
Maintenance phase: nivolumab** OR | 3 mg/kg | IV infusion 30 min. | every 14 days | Continuously | |
Maintenance phase: nivolumab** OR | 240 mg | IV infusion 30 min. | every 14 days | Continuously | |
Maintenance phase: nivolumab** | 480 mg | IV infusion 30 min. | Once every 28 days | Continuously | |
Combination therapy with CTLA-4 mAb and PD-1 mAb (IPI 1 / PEMBRO 200) [438] (Level of recommendation – C) (level of evidence – 4). | Pembrolizumab** (on the same day as ipilimumab**) | 200 mg | IV infusion 30 min. | every 21 days | Total of no more than 4 administrations |
Ipilimumab** (on the same day as pembrolizumab**) | 1 mg/kg | IV infusion 30 min. | every 21 days | Total of no more than 4 administrations | |
Maintenance phase: pembrolizumab** OR | 200 mg | IV infusion over 30 min | every 21 days | Continuously | |
Maintenance phase: pembrolizumab** | 400 mg | IV infusion 30 min. | Once every 42 days | Continuously |
If there are signs of disease progression during monotherapy with BRAF inhibitors, switching adult patients to combination therapy with a BRAF inhibitor + MEK inhibitor is not recommended, as the likelihood of achieving a treatment response remains low, and the median progression-free survival does not exceed 3 months [179].
GCP CLEL 3Grade of Recommendation – C (Level of Evidence – 3).
If there are signs of disease progression during therapy with a single BRAF inhibitor or a single combination of a BRAF inhibitor and a MEK inhibitor (Table 12), it is not recommended to switch adult patients to another BRAF inhibitor or another combination of a BRAF inhibitor and a MEK inhibitor [439-441].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: available preclinical data suggest similar mechanisms of action and resistance development for vemurafenib**/cobimetinib** and dabrafenib**/trametinib**. There is also a lack of data regarding the clinical efficacy of such a switch.
In slowly progressing metastatic and/or locally advanced melanoma (stage III unresectable – stage IV) in adult patients with an expected life expectancy of at least 6 months, in the absence of contraindications, regardless of BRAF mutation status, the use of ipilimumab** [442] or a combination of PD-1 and CTLA-4 mAbs is recommended after disease progression on standard therapy (PD-1 mAbs, BRAF inhibitors, BRAF + MEK inhibitor combination) or in case of its intolerance [443-447]. The administration regimen for ipilimumab** is provided below (Table 14).
GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).
Table 14. Administration regimen of ipilimumab** for cutaneous melanoma in adult patients.
Therapy regimen | Drug | Dose | Route of administration | Administration days | Cycle duration, days, schedule |
|---|---|---|---|---|---|
Monotherapy [409,411,414,420,442-444,446-449] | Ipilimumab** | 3 mg/kg of body weight | IV infusion over 90 min. | every 21 days | Maximum of 4 administrations |
If therapy with a BRAF inhibitor, a BRAF + MEK inhibitor combination, PD-1 mAbs, or CTLA-4 mAbs in the 1st or 2nd line cannot be administered (or if the waiting time for such therapy exceeds 1 month) in patients with metastatic or unresectable melanoma and a BRAF gene mutation in the tumor, while maintaining a satisfactory general condition of the adult patient (ECOG 0–2) and an expected life expectancy of more than 3 months, cytotoxic chemotherapy is recommended [450-458]. The most common chemotherapy regimens (monotherapy or combinations) are provided below (Table 15). The prescription of other medicinal products for the treatment of disseminated melanoma is decided by a medical board or a consilium of physicians.
ROB BLOE 1Recommendation grade – B (evidence level – 1).
Comment: this type of treatment is less effective in terms of increasing overall survival, progression-free survival, and objective response rate, and in most cases is accompanied by more pronounced adverse reactions compared to BRAF inhibitors, BRAF + MEK inhibitor combinations, or PD-1 or CTLA-4 mAbs. Therefore, the use of chemotherapy in the 1st-line treatment of patients with metastatic or unresectable melanoma and a BRAF gene mutation should be avoided whenever possible.
Table 15. Most common chemotherapy regimens for metastatic cutaneous melanoma in adults.
Therapy regimen | Drug | Dose | Route of administration | Administration days | Cycle duration, days, schedule | Reference |
|---|---|---|---|---|---|---|
Monotherapy | Dacarbazine** | 1000 mg/m2 | IV | 1st | 21 | [176,219,450-452,459,460] |
Monotherapy | Dacarbazine** | 250 mg/m2 | IV | 1st–5th | 21 | |
Monotherapy | Temozolomide** | 200 mg/m2 | orally or IV | 1st–5th | 28 | [453,461] |
Monotherapy | Lomustine** | 130 mg/m2 | orally | 1st | 42 | [462-464] |
Combination | Cisplatin** | 20 mg/m2 | IV | 1st–4th | 21 (2 cycles and evaluation, up to a maximum of 6 cycles) | [457,458,465,466] |
Vinblastine** | 1.2–2 mg/m2 | IV | 1st–4th | |||
Dacarbazine** | 800 mg/m2 | IV | 1st | |||
Combination | #Paclitaxel** | 225 mg/m2 | IV | 1st | 21 | [281][467][388] |
#Carboplatin** | AUC 6 | IV | 1st | |||
Combination | #Paclitaxel** | 175 mg/m2 | IV | 1st | 21 | [455,456,468] |
#Carboplatin** | AUC 5-6 | IV | 1st |
During chemotherapy, treatment efficacy assessment is recommended to be performed after every 2nd–3rd cycle (every 6–12 weeks). To assess therapy efficacy, it is recommended to use the patient's general condition assessment and diagnostic imaging methods (Table 9, Section 2.4), as well as standard response criteria for cytostatic therapy (RECIST 1.1, Appendix G3) [430,431].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
When administering systemic antineoplastic therapy, when calculating drug doses based on body surface area or body weight, it is recommended to round actual doses within 5% of the calculated doses [469,470].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
In case of progression after first-line therapy with a single PD-1 monoclonal antibody inhibitor in adult patients with cutaneous melanoma carrying a BRAF gene mutation, it is recommended to prioritize monotherapy with a CTLA-4 inhibitor or combination therapy with BRAF and MEK inhibitors [433,449,471–473].
GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).
Comment: a study by I.P. da Silva et al. demonstrated an increase in the objective response rate from 9% with ipilimumab** monotherapy to 38% with combination therapy of ipilimumab** and nivolumab** in patients without a BRAF gene mutation. In patients with the mutation, response rates were similar (24% and 19%, respectively) [449].
In adult patients with BRAF-mutated melanoma (unresectable stage III to stage IV) in the 3rd line of therapy, after immunotherapy and inhibitor therapy of BRAF (iBRAF +/- MEK), as well as in patients without a BRAF gene mutation (unresectable stage III to stage IV) in the 2nd line of therapy after immunotherapy (PD-1 monoclonal antibody inhibitors +/- anti-CTLA-4) with documented acquired resistance to aPD-1 (stabilization or response to aPD-1 >= 6 months), it is recommended to use the regimen of #lenvatinib** + pembrolizumab** [474–476]. The administration regimen is provided below (Table 16).
GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).
Table 16. Combination therapy with PD-1 monoclonal antibody inhibitors and the TKI #lenvatinib** in adults.
Therapy regimen | Drug | Dose | Route of administration | Administration days | Cycle duration, days, schedule |
|---|---|---|---|---|---|
Combination therapy with PD-1 monoclonal antibody inhibitors and the TKI lenvatinib [474] | Pembrolizumab** | 200 mg | IV infusion over 30 min | every 21 days | prolonged |
#Lenvatinib** 20 mg orally | 20 mg | orally | once daily, every day | prolonged |
It is recommended to re-administer combination therapy with BRAF and MEK inhibitorsK in adult patients who previously received long-term (more than 6 months) therapy with BRAF and MEK inhibitors and who achieved an objective response to treatment, in case of disease progression or intolerance to PD-1 monoclonal antibody inhibitors or the combination of PD-1 and CTLA-4 monoclonal antibody inhibitors administered in the second line [225,477].
GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).
It is recommended to continue combination therapy with BRAF and MEK inhibitors or monotherapy with PD-1 monoclonal antibody inhibitors in patients with isolated progression of individual metastases with the possibility of their surgical resection or stereotactic radiosurgery for the progressing lesions ("oligoprogression") [220,478–485].
GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).
In adult patients with a BRAF gene mutation in the absence of contraindications, it is recommended to administer combination chemo- and targeted immunotherapy with a PD-1 monoclonal antibody inhibitor (pembrolizumab**) and protein kinase inhibitors dabrafenib** and trametinib** [486].
Administration regimens are provided below (Table 17).
GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).
Comment: the combination of pembrolizumab**, dabrafenib**, and trametinib** was studied in patients with BRAF-mutated melanoma in the first-line setting and showed a numerical improvement over combination targeted therapy with dabrafenib** and trametinib** in terms of progression-free survival, though this improvement did not reach statistical significance. (At a median follow-up of 36.6 months, median progression-free survival was 16.9 months in the triple combination group and 10.7 months in the targeted therapy group [HR 0.53; 95% CI 0.34 to 0.83]. Overall survival also showed a trend toward improvement in the triple combination group [non-significant].) We believe that the triple combination may be preferable to therapy with dabrafenib** and trametinib** in a specific subset of patients with a BRAF gene mutation; however, there is currently insufficient scientific data to define this subset of patients more precisely. The oncologist should weigh all potential risks and expected benefits when prescribing this treatment regimen.
Table 17. Administration regimens for the aPD-1 monoclonal antibody inhibitor pembrolizumab** and inhibitors dabrafenib** and trametinib** in adults.
Regimen | Drug | Dose | Route of administration | Days of administration | Cycle duration, days, schedule |
|---|---|---|---|---|---|
Pembrolizumab** + dabrafenib** + trametinib** | Dabrafenib** | 150 mg twice daily | Oral | Daily | Continuously |
Trametinib** | 2 mg once daily | Oral | Daily | Continuously | |
Pembrolizumab** | 200 mg | Intravenously | Day 1, 22 | Every 21 days |
3.4.3. Selection of therapy in patients with metastatic or unresectable cutaneous melanoma with a KIT gene mutation
In adult patients with a KIT gene mutation and an expected life expectancy of more than 3 months, monotherapy with PD-1 monoclonal antibody blockers or a combination of CTLA-4 and PD-1 monoclonal antibody blockers is recommended as first-line or subsequent-line therapy [410,414,416,417,420,487]. Standard administration regimens are provided above (Table 13).
GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).
Comment: the patient population with a KIT gene mutation in the tumor has not been studied separately in randomized trials; however, it should be considered as a population of patients without a BRAF gene mutation.
In adult patients with a KIT gene mutation and an expected life expectancy of more than 3 months, therapy with KIT TKIs, #imatinib**, is recommended as second-line or subsequent-line therapy. Treatment with #imatinib** is administered until disease progression or the development of severe toxicities that cannot be managed by dose reduction. The administration regimen is provided below (Table 18) [199,200].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
Table 18. Administration regimen of #imatinib** in cutaneous melanoma.
Therapy regimen | Drug | Dose | Route of administration | Administration days | Cycle duration, days, schedule |
|---|---|---|---|---|---|
Monotherapy | #Imatinib** | 400 mg twice daily | Oral | Daily | Continuously until progression |
Evaluation of the efficacy of therapy with #imatinib** TKIs is recommended at least once every 6–8 weeks of therapy, without interrupting the drug intake during the response assessment period. To evaluate treatment efficacy, it is recommended to use the assessment of the patient's general condition and diagnostic imaging methods (Table 9), as well as standard response criteria for cytotoxic therapy (RECIST 1.1) [191,199,430,431].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
It is not recommended to administer #imatinib** therapy to patients with unknown tumor status regarding the KIT gene mutation, as there is no data on the clinical benefit of #imatinib** in patients without an activating KIT gene mutation [200,203,488,489].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
In the presence of signs of disease progression during #imatinib** therapy, while maintaining a satisfactory general condition of the adult patient (ECOG 0–2) and an expected life expectancy of more than 3 months, therapy with PD-1 and/or CTLA-4 monoclonal antibody blockers is recommended (if it has not been administered previously) [490,491].
Administration regimens are provided above (Table 13, Table 14).
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
If #imatinib** or PD-1 and/or CTLA-4 monoclonal antibody blockers cannot be administered (or if the waiting period for the start of such therapy exceeds 1 month) as first- or second-line treatment in adult patients with metastatic or unresectable melanoma with a KIT gene mutation in the tumor, while maintaining a satisfactory general condition of the patient (ECOG 0–2) and an expected life expectancy of more than 3 months, cytotoxic chemotherapy is recommended [415,450-458,466]. The most common chemotherapy regimens (monotherapy or combinations) are provided above (Table 15). The prescription of other medicinal products for the treatment of disseminated melanoma is decided by a medical board or a medical commission.
GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).
Comment: this type of treatment is less effective in terms of increasing overall survival, progression-free survival, and objective response rate, and in most cases is accompanied by more pronounced adverse reactions compared to KIT TKIs or PD-1 or CTLA-4 monoclonal antibody blockers. Therefore, the use of chemotherapy in the first-line treatment of patients with metastatic or unresectable melanoma and a KIT or NRAS gene mutation should be avoided whenever possible.
In adult patients without BRAF and KIT gene mutations, while maintaining a satisfactory general condition of the patient (ECOG 0–2) and an expected life expectancy of more than 3 months, therapy with a combination of PD-1 and CTLA-4 monoclonal antibody blockers or monotherapy with PD-1 monoclonal antibody blockers is recommended [410,414,416,417,420,487]. Standard administration regimens are provided above (Table 13).
GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).
In case of overt disease progression during therapy with one of the PD-1 monoclonal antibody blockers, it is recommended to consider therapy with a combination of PD-1 and CTLA-4 monoclonal antibody blockers [492] or monotherapy with a CTLA-4 monoclonal antibody blocker [442,493].
Administration regimens are provided above (Table 13, Table 14).
GOR BLOE 3Grade of Recommendation – B (Level of Evidence – 3).
If PD-1 and CTLA-4 monoclonal antibody blockers cannot be administered as first- or second-line therapy (or if the waiting period for the start of such therapy exceeds 1 month) in adult patients with metastatic or unresectable melanoma without BRAF and KIT gene mutations in the tumor, while maintaining a satisfactory general condition of the patient (ECOG 0–2) and an expected life expectancy of more than 3 months, cytotoxic chemotherapy is recommended [450-458]. The most common chemotherapy regimens (monotherapy or combinations) are provided above (Table 15). The prescription of other medicinal products for the treatment of disseminated melanoma is decided by a medical board or a medical commission.
ROB BLOE 1Recommendation grade – B (evidence level – 1).
Comment: this type of treatment is less effective in terms of increasing overall survival, progression-free survival, and objective response rate, and in most cases is accompanied by more pronounced adverse reactions compared to PD-1 or CTLA-4 monoclonal antibody blockers. Therefore, the use of chemotherapy in the first-line treatment of patients with metastatic or unresectable melanoma without BRAF and KIT gene mutations should be avoided whenever possible.
In adult patients progressing after adjuvant therapy with one of the PD-1 monoclonal antibody blockers, it is recommended to prioritize the combination of PD-1 monoclonal antibody blockers and CTLA-4 blockers [449].
GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).
Comment: a study by I.P. da Silva et al. demonstrated an increase in the objective response rate from 13% with ipilimumab** monotherapy to 36% with combination therapy of ipilimumab** and nivolumab** [449].
In patients with no BRAF gene mutation progressing after first-line therapy with one of the PD-1 monoclonal antibody blockers, it is recommended to prioritize the combination of PD-1 monoclonal antibody blockers and CTLA-4 blockers [449].
GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).
Comment: a study by I.P. da Silva et al. demonstrated an increase in the objective response rate from 9% with ipilimumab** monotherapy to 38% with combination therapy of ipilimumab** and nivolumab** in patients without a BRAF gene mutation. In the presence of a mutation, response rates were similar (24% and 19%, respectively) [449].
In adult patients with or without a BRAF gene mutation progressing during therapy with one of the PD-1 monoclonal antibody blockers, re-administration of PD-1 monoclonal antibody blockers (or administration of combination therapy with PD-1 and CTLA-4 monoclonal antibody blockers) is recommended provided 4 conditions are met: 1) disease control (objective response or stabilization) upon the first administration of PD-1 monoclonal antibody blockers was 6 months or more; 2) second-line (or subsequent-line) treatment no longer provides benefit (disease progression or treatment intolerance is observed); 3) patient's ECOG performance status <= 2 or expected life expectancy > 3 months; 4) previous adverse events associated with the use of PD-1 monoclonal antibody blockers have resolved (<= grade 1 according to CTCAE v5.0) AND never reached grade 4 according to CTCAE v5.0 [494].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
In adult patients without a BRAF gene mutation (stage III unresectable to stage IV) in the second line after immunotherapy (PD-1 +/- anti-CTLA-4 monoclonal antibody blockers), given the low efficacy of chemotherapy, therapy with #lenvatinib** + pembrolizumab** is recommended [474-476]. The administration regimen is provided above (Table 16).
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
3.4.5. Specifics of response evaluation to PD1 or CTLA4 monoclonal antibody blockers
PD-1 or CTLA-4 monoclonal antibody blockers represent a fundamentally new class of medicinal products whose effect develops as a result of interaction with elements of the patient's immune system. The medicinal products themselves do not have an antitumor effect, and the elimination of tumor cells is achieved by activating the patient's immune system cells. This determines the specific features of the clinical and radiological response to treatment.
All melanoma patients receiving therapy with PD-1 or CTLA-4 monoclonal antibody blockers are recommended to undergo an initial radiological evaluation of treatment response no earlier than 12 weeks from the start of therapy (in the absence of clinical deterioration of the patient's condition). Subsequent evaluations are performed every 8–12 weeks (in the absence of clinical deterioration of the patient's condition) [414,416,417,487,495].
GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).
It is recommended to use modified response criteria for treatment evaluation with PD-1 or CTLA-4 monoclonal antibody blockers, which allow for the appearance of new lesions (in the absence of clinical deterioration of the patient's condition) [495] (Table 19).
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Table 19. Comparison of traditional criteria (using RECIST as an example) and response evaluation criteria for mAb PD-1 or CTLA-4 blockers (mRECIST or irRC) [495-497].
Tumor response | RECIST | irRC |
|---|---|---|
Complete response | Disappearance of all target lesions | Disappearance of all lesions, including new ones |
Partial response | Decrease in the sum of maximum diameters of target lesions by more than 30% with no progression of other lesions or appearance of new ones | Decrease in the sum of products of perpendicular diameters of target and new lesions by more than 30%. Appearance of new lesions is allowed |
Stable disease | Decrease in tumor formations by less than 30% or increase by no more than 20% in the absence of new lesions | Decrease in tumor formations by less than 30% in the absence of new lesions or increase by no more than 20%. Appearance of new lesions is allowed |
Progressive disease | Increase in the sum of maximum diameters of target lesions by more than 20% and/or appearance of new lesions | Increase in the sum of products of perpendicular diameters of target and new lesions by more than 20% |
3.4.6. Duration of treatment with PD1 or CTLA4 monoclonal antibody blockers
It is recommended that adults receive a CTLA-4 mAb blocker (ipilimumab**) in a limited number of administrations—no more than 4. In certain cases (with disease stabilization or objective response to treatment for more than 6 months, followed by disease progression), a repeated course of ipilimumab** treatment is permitted (also no more than 4 administrations) [443].
LoR CLE 2Level of Recommendation – C (Level of Evidence – 2).
It is recommended that PD-1 mAb blockers in adults be prescribed on a continuous schedule until disease progression, intolerance, or the expiration of 2 years from the date of the first therapy cycle, with an administration interval of 2 weeks or 4 weeks for nivolumab**, depending on the dosing regimen, 3 or 6 weeks for pembrolizumab**, and once every 14 days for proлголимаб** (prolgolimab**). Continuation of therapy beyond 2 years is possible in individual clinical situations by decision of the medical panel (see also section 3.4.5 and Table 13) [414,416,417,435,436,448,487].
GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).
Comment: in the KEYNOTE-006 trial, the duration of immunotherapy regimens in patients with metastatic melanoma who maintained clinical benefit did not exceed 24 months, which may indicate that it is safe to discontinue therapy in patients achieving a response after 24 months of treatment.
3.4.7. Treatment of patients with special forms of metastatic melanoma: oligometastatic, locally advanced, with bone metastases
Patients with solitary distant metastases of melanoma (to soft tissues, lungs, brain, etc.) and good performance status are recommended to be considered as candidates for radical surgical treatment, which can provide a prolonged disease-free interval [498-500].
GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).
Comments: the role of surgery is increasing due to the availability of effective adjuvant therapy with the PD-1 mAb blocker nivolumab** for this patient group, which demonstrated an increase in disease-free survival compared to observation in a randomized trial [352].
Upon achieving a response to ongoing systemic therapy, complete cytoreductive interventions may be considered. Incomplete cytoreduction is not recommended [501,502].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Patients with locally advanced unresectable cutaneous melanoma and isolated limb involvement who have not responded to standard therapy (BRAF or MEK inhibitors, PD-1 or CTLA-4 mAb blockers) are recommended to be considered as candidates for isolated hyperthermic limb perfusion with melphalan** [503-506].
GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).
Comment: this procedure is performed in selected specialized centers.
For extensive facial skin lesions (lentigo maligna melanoma) in adult patients who decline reconstructive and plastic surgery of the face, it is recommended to use #imiquimod cream as a means to reduce the area of lentigo maligna in the preoperative period (5 times a week for 3 months using 5% #imiquimod cream prior to excision) [507-509].
GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).
For stage 0 lentigo maligna melanoma in adult patients who decline reconstructive and plastic surgery of the face, it is recommended to use #imiquimod cream as a monotherapy treatment (daily for 3 months using 5% #imiquimod cream) [507-509].
GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).
For regional lymph node metastases where surgical removal is impossible, it is recommended to consider external beam radiotherapy in various regimens: 50 Gy in 20 fractions over 4 weeks; 32 Gy in 4 fractions over 4 weeks [258].
LoR CLE 2Level of Recommendation – C (Level of Evidence – 2).
Comment: a radiotherapy regimen of 30 Gy in 10 fractions over 2 weeks may also be used [510].
For symptomatic bone metastases with an analgesic goal, it is recommended to administer palliative radiotherapy in one of the following regimens: 30 Gy in 10 fractions over 2 weeks; 20 Gy in 5 fractions over 5–7 days, 24 Gy in 6 fractions over 3 weeks [258,510-512].
GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).
3.4.8. Treatment of patients with brain metastases
Introduction: The incidence of brain metastases in patients with generalized melanoma reaches 28%, exceeding that in patients with non-small cell lung cancer (26.8%) and HER2-positive breast cancer (11.5%). Given the specific disease course in CNS involvement, clinical guidelines feature a separate section on the management strategy for patients with CNS metastases.
It is recommended to formulate the treatment selection algorithm for patients with brain metastases during a multidisciplinary team meeting involving a neurosurgeon, radiation oncologist, and oncologist based on the following criteria [134-136,513-515]:
extracranial disease spread and its control;
availability of systemic antineoplastic therapy reserves;
size of brain metastases (greater or less than 2 cm);
number of brain metastases (solitary metastasis, oligometastatic disease (2–4 metastases), multiple metastases (5 or more));
general condition according to the Karnofsky performance scale (greater than 70%, less than 70%) (Appendix G2);
overall survival prognosis (more or less than 6 months according to the GPA scale (online calculator at https://brainmetgpa.com/), Appendix G4);
location of metastases in functionally critical brain regions;
presence or absence of neurological symptoms caused by metastatic brain involvement.
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: radiotherapy should be considered in patients with newly diagnosed brain metastases of melanoma as a standalone treatment option or as a component of a combined treatment approach (with a neurosurgical stage), as well as in patients with intracranial progression (local recurrences or development of new distant metastases) after prior treatment. Options for radiotherapy in the management of patients with melanoma brain metastases include stereotactic radiosurgery/radiotherapy (SRT) and whole-brain radiotherapy (WBRT). SRT can be delivered in radiosurgery mode (1 fraction) or hypofractionation (3 to 7 fractions) and is used as a standalone treatment or in combination with WBRT or neurosurgery [1,2]. Radiotherapy is not recommended in patients with asymptomatic brain metastases and poor functional status (Karnofsky index of 50% or lower) or in patients with a Karnofsky index < 70%, extracranial disease progression, and no reserves of systemic antineoplastic therapy. The choice of the SRT fractionation regimen depends on the radiation dose load to normal brain tissue, which is determined by the number and size of melanoma brain metastases. SRT in radiosurgery mode can be performed provided that, with a target dose of 20-24 Gy, the volume of normal brain tissue irradiated with a dose of 12 Gy does not exceed 10 cm3 (V12Gy ≤ 10 cm3). For any melanoma brain metastases where V12Gy > 10 cm3, SRT in a hypofractionated regimen is indicated [134-136].
It is recommended to perform open neurosurgery in patients with newly diagnosed or recurrent cranial melanoma metastases in the presence of:
a metastatic lesion with a maximum diameter of 2 cm or more;
a metastatic lesion of any size that determines the clinical picture of intracranial hypertension, dislocation of midline brain structures, extensive perifocal edema, and poses a threat of cerebrospinal fluid pathway blockage;
clinical situations that cannot be controlled by other therapeutic measures (radioresistant local recurrence after stereotactic radiosurgery, symptomatic radionecrosis resistant to ongoing therapy) [134].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comments: a prerequisite for neurosurgical treatment is the localization of the metastatic lesion in brain regions where its removal does not cause or worsen neurological deficits. The best overall survival rates are achieved in patients with a high functional status (Karnofsky performance scale ≥ 80) and controlled extracranial tumor disease. In patients with newly diagnosed or recurrent brain metastases from melanoma, it is advisable to combine neurosurgical treatment with stereotactic radiotherapy (preoperative radiosurgery or postoperative stereotactic radiotherapy of the resection cavity) to reduce the risk of local recurrence. It is advisable to perform brain CT with/without contrast within 24–48 hours after neurosurgical resection to diagnose postoperative hemorrhage.
In patients with 1 to 4 brain metastases and a favorable overall survival prognosis according to the GPA score, it is recommended to perform stereotactic radiosurgery (SRS) for brain metastatic lesions with a maximum diameter of 2.0 cm or less without clinical manifestations of mass effect [135,136].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comments: a favorable overall survival prognosis is determined by a high functional status (Karnofsky performance scale ≥ 80 or ECOG 0–1), a GPA survival estimate of 6 months or more, stabilization of extracranial metastases, and/or available reserves of systemic antineoplastic therapy. SRS in radiosurgery mode is the optimal treatment option in patients with lesions < 2 cm in maximum dimension and a delivered marginal radiation dose of 20–24 Gy. In patients with lesions ≥ 2 cm in maximum dimension, SRS in radiosurgery mode can be performed provided that with a marginal radiation dose of at least 20 Gy, the volume of normal brain tissue irradiated with 12 Gy does not exceed 10 cm3 (V12Gy ≤ 10 cm3).
It is recommended to perform fractionated stereotactic radiotherapy (FSRT) in the presence of brain metastatic lesions with a maximum diameter of 2.0 cm or greater, without clinical manifestations of mass effect and in the presence of contraindications to neurosurgery [135,136,513].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
Comments: FSRT is the optimal option in patients with lesions ≥ 2 cm in maximum dimension, or with lesions localized in critical brain structures (optic pathways, brainstem, etc.). Recommended fractionation regimens are: 3 fractions at a dose per fraction of 8 Gy / 9 Gy, 5 fractions at 6 Gy, and 7 fractions at 5 Gy. During fractionated irradiation, dose constraints must be observed: a volume of 10 cm3 of normal brain tissue must not be irradiated with a dose exceeding 19.2 Gy (in 3 fractions), 23.4 Gy (in 5 fractions), and 26.5 Gy (in 7 fractions).
In patients with 5 or more brain metastases from melanoma and a favorable overall survival prognosis, it is recommended to perform SRS in radiosurgery or fractionated mode, or whole-brain radiotherapy (WBRT) [135,136].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comments: in patients with multiple brain metastases from melanoma and a favorable overall survival prognosis (isolated intracranial progression, absence or stabilization of extracranial metastases, available reserves of systemic drug therapy), SRS in radiosurgery or radiotherapy as a standalone treatment option is preferred. Regular brain MRI is required for early detection of intracranial progression and subsequent local treatment (neurosurgery and/or radiotherapy). Standalone WBRT should be considered in patients with progressive multiple, disseminated, or leptomeningeal brain involvement where stereotactic radiotherapy and neurosurgery are unfeasible, as well as in cases of failure of antineoplastic drug therapy and lack of systemic treatment reserves. Standard total doses for WBRT are 20 Gy (in 5 fractions), 30 Gy (in 10 fractions), 37.5 Gy (in 15 fractions). The use of WBRT as a component combined with SRS reduces the risk and delays the development of new (distant) brain metastases, but does not improve overall survival and increases the risk of cognitive impairment. In cases combining stereotactic radiosurgery followed by WBRT, it is advisable to reduce the stereotactic radiosurgery doses by 20–25% from the initial radiation dose to minimize the risk of post-radiation changes [135,136].
In patients with a favorable overall survival prognosis following neurosurgical resection of brain metastases, it is recommended to perform postoperative SRS of the resection cavity in radiosurgery or fractionated mode [135,136].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comments: SRS in radiosurgery or fractionated mode after neurosurgery is performed 4 to 6 weeks post-resection. Prior to radiotherapy, a brain MRI is performed to assess the size of the postoperative cavity, presence of midline shift, and appearance or growth of new or existing unresected brain metastases. Fusion with the preoperative MRI is mandatory, after which the target volume is defined: postoperative cavity + 2 mm margin (+ 5 mm along the dura mater) and contrast-enhancing areas of unresected metastatic lesions without a margin. For patients scheduled for neurosurgical resection of brain metastases, preoperative radiosurgery may serve as an alternative to postoperative SRS in radiosurgery or fractionated mode.
In patients with an unfavorable overall survival prognosis, it is recommended to provide supportive care [135,136].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comments: an unfavorable overall survival prognosis is determined by a low functional status (Karnofsky performance scale ≤ 70 or ECOG 3–4), a GPA survival estimate of less than 6 months, presence of extracranial progression, and lack of systemic antineoplastic treatment reserves. In certain clinical situations, local treatment (neurosurgery and/or radiotherapy) may be performed to alleviate neurological disorders. The decision to perform local treatment must be made by a multidisciplinary team, taking into account potential clinical efficacy and potential treatment risks for the patient.
In patients with large brain metastases from melanoma (or lesions of any size with peritumoral edema) who are candidates for antineoplastic drug therapy with established CNS efficacy, it is recommended to administer upfront local therapy (neurosurgery or stereotactic radiotherapy) [134].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comments: in selected patients with large brain metastases from BRAF-mutant melanoma (or brain metastases of any size with peritumoral edema) requiring steroid therapy, in the absence of life-threatening neurological disorders and the inability to perform local treatment (neurosurgery, SRS in radiosurgery or fractionated mode), combined targeted therapy with BRAF and MEK inhibitors may be administered as the first-line treatment [435].
Drug therapy for patients with brain metastases is carried out according to the same principles as for patients with metastases in other locations.
In adult patients with stable brain metastases from melanoma, it is recommended to prioritize combination immunotherapy (monoclonal antibodies blocking CTLA-4 and PD-1) over monotherapy with PD-1 or CTLA-4 blocking monoclonal antibodies [409,411].
GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).
In the presence of a V600 mutation in the BRAF gene in adult patients with melanoma and brain metastases, it is recommended to prioritize combination targeted therapy with BRAF and MEK inhibitors over BRAF inhibitor monotherapy [222,516] (Table 12).
GCP CLEL 3Grade of Recommendation – C (Level of Evidence – 3).
In adult patients with a BRAF gene mutation (with an equivalent of stage IV M1d and the presence of neurological symptoms) in the absence of contraindications, it is recommended to administer combined immunotherapy and targeted therapy with PD-L1 blocking monoclonal antibodies (atezolizumab**) and the protein kinase inhibitors vemurafenib** and cobimetinib** [218]. Treatment regimens are provided below (Table 20).
GCP CLEL 3Grade of Recommendation – C (Level of Evidence – 3).
Comment: the combination of atezolizumab**, vemurafenib**, and cobimetinib** was evaluated in patients with BRAF-mutated melanoma in the first-line setting and showed borderline superiority over combined targeted therapy with vemurafenib** and cobimetinib** in terms of progression-free survival. We believe that the triplet combination may be preferred over vemurafenib** and cobimetinib** therapy in a certain subset of patients with a BRAF gene mutation; however, there is currently insufficient scientific data to precisely define this subset of patients. Oncologists should weigh all potential risks and expected benefits when prescribing this treatment regimen.
Table 20. Dosing regimens of the PD-L1 mAb inhibitor atezolizumab** and the kinase inhibitors vemurafenib** and cobimetinib** in adults.
Regimen | Drug | Dose | Route of administration | Days of administration | Cycle duration, days, schedule |
|---|---|---|---|---|---|
Atezolizumab** + vemurafenib** + cobimetinib** [217,218,423,517] | Vemurafenib** | 960 mg twice daily | Oral | Daily days 1-21 | Day 1-21 (lead-in period of combined targeted therapy) |
Cobimetinib** | 60 mg once daily | Oral | Daily days 1-21 | Day 1-21 (lead-in period of combined targeted therapy) | |
Vemurafenib** | 720 mg twice daily | Oral | Daily days 22-28 | Day 22-28 (lead-in period of combined targeted therapy) | |
Atezolizumab** OR (!) | 840 mg | IV infusion | Day 1 (29), 15 (44) | Starting from day 29 of the cycle, every 1st and 15th day | |
Atezolizumab** | 1200 mg | IV infusion | Day 1 (29), 22 | Starting from day 29 of the cycle every 3 weeks | |
OR (!) Atezolizumab** | 1680 mg | IV infusion | Day 1 (29) | Starting from day 29 of the cycle every 4 weeks | |
Vemurafenib** | 720 mg twice daily | Oral | Daily days 1-28 | Day 1-28 (triplet combination treatment period) | |
Cobimetinib** | 60 mg once daily | Oral | Daily days 1-21 | Day 1-21 (triplet combination treatment period) | |
Vemurafenib** 960 mg (four 240 mg tablets) orally twice daily with cobimetinib** 60 mg (three 20 mg tablets) orally once daily on days 1 to 21, followed by vemurafenib** 720 mg (three 240 mg tablets) orally twice daily on days 22 to 28. Triplet combination period (from day 29 onwards): atezolizumab** 840 mg intravenously on days 1 and 15, cobimetinib** 60 mg (three 20 mg tablets) orally once daily on days 1 to 21, vemurafenib** 720 mg (three 240 mg tablets) orally twice daily on days 1 to 28 of a 28-day cycle. Treatment is administered until disease progression or unacceptable toxicity. If necessary, the lead-in period (treatment with vemurafenib** and cobimetinib** combination only) may be extended up to 56 days, and the atezolizumab** administration schedule may be changed to atezolizumab** 1200 mg intravenously on day 1 every 21 days or atezolizumab** 1680 mg intravenously on day 1 every 28 days. | |||||
In the presence of a V600 mutation in the BRAF gene in patients with melanoma brain metastases and neurological symptoms, it is recommended to prioritize combined immuno-targeted therapy with BRAF and MEK inhibitors and anti-PD-L1 therapy [217,518] (see also Table 13).
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
It is not recommended to administer steroid therapy in patients with melanoma brain metastases without clinical symptoms and manifestations of mass effect [57,519-523].
LoR CLE 2Level of Recommendation – C (Level of Evidence – 2).
Comments: in patients with melanoma brain metastases and neurological symptoms associated with mass effect, steroid therapy (dexamethasone**) is recommended to eliminate or temporarily relieve symptoms associated with increased intracranial pressure and secondary brain edema. The dose of steroid therapy should be the minimum necessary to control symptoms and is typically 4–8–12 mg/day.
When administering immunotherapy (CTLA-4, PD-1, and PD-L1 inhibitors), it is not recommended to exceed a dexamethasone** dose of more than 4 mg per day. An alternative option for anti-edema therapy in this clinical situation is the administration of #bevacizumab** (see Table 21).
It is recommended to administer #bevacizumab** therapy in the presence of symptomatic perifocal edema of metastatic lesions or radionecrosis resistant to ongoing steroid therapy, or if there are contraindications to steroid therapy (e.g., when concurrent therapy with PD-1/PD-L1 monoclonal antibody inhibitors or CTLA-4 monoclonal antibody inhibitors is required) (see also Table 21) [57,519-522,524].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
Table 21. Recommended dosing regimens for #bevacizumab** in symptomatic perifocal edema or brain radionecrosis.
Therapy regimen | Drug | Dose | Route of administration | Administration days | Cycle duration, days, schedule |
|---|---|---|---|---|---|
Monotherapy [520] | #Bevacizumab** | 5 mg/kg of body weight | IV infusion | every 14 days | Long-term (from 4 administrations until regression of neurological symptoms, improvement in radiological findings, or occurrence of intolerance) |
Monotherapy [520] | #Bevacizumab** | 7.5 mg/kg of body weight | IV infusion | Once every 21 days | Long-term (from 4 administrations until regression of neurological symptoms, improvement in radiological findings, or occurrence of intolerance) |
3.4.9. Concurrent use of radiation therapy and systemic antineoplastic treatment
Since there is evidence of a radiosensitizing effect of BRAF and MEK inhibitors in cases of severe visceral toxicity when administered concurrently with radiation therapy, it is recommended that all melanoma patients discontinue BRAF or MEK inhibitors:
at least 3 days before the start of radiation therapy and resume no earlier than 3 days after the completion of fractionated radiation therapy;
at least 1 day before the start of stereotactic radiosurgery (or radiotherapy) and resume 1 day after its completion [525-528].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Currently, there is no convincing data indicating impaired treatment tolerability with concurrent radiation therapy and PD-1 or CTLA-4 monoclonal antibody inhibitor therapy. Analysis of the presented study results has shown that radiation therapy is recommended in combination with PD-1 or CTLA-4 monoclonal antibody inhibitor therapy without loss of efficacy and without an increased rate of adverse reactions [525,528-530].
GCP CLEL 3Grade of Recommendation – C (Level of Evidence – 3).
3.4.10. Approaches to the treatment of patients after complete resection of all metastatic lesions (Stage IV equivalent, no evidence of disease)
It is recommended for adult patients after complete (R0) resection of distant cutaneous melanoma metastases or melanoma metastases of unknown primary site (in soft tissues, lungs, brain, etc.) within 3 months after surgical treatment in the absence of contraindications to receive adjuvant therapy with nivolumab** according to the schedule: nivolumab** 3 mg/kg every 2 weeks as an IV infusion for 12 months (Level of Evidence A, Grade of Recommendation 2) or nivolumab** 240 mg every 2 weeks as an IV infusion for 12 months, or nivolumab** 480 mg IV every 4 weeks for 12 months (Level of Evidence C, Grade of Recommendation 5) [352,368,369,434,531,532].
LoR ALoE 2Level of Recommendation – A (Level of Evidence – 2) - for 3 mg/kg every 2 weeks as an IV infusion for 12 months.
LoR CLoE 5Level of Recommendation – C (Level of Evidence – 5) - for 240 mg every 2 weeks as an IV infusion for 12 months and 480 mg IV every 4 weeks for 12 months.
It is recommended for adult patients with metastatic melanoma (M1 stage equivalent) after surgical removal of all metastatic nodes, with no evidence of disease, to receive adjuvant combination therapy with CTLA-4 monoclonal antibody inhibitors and PD-1 monoclonal antibody inhibitors [533,534]. The administration regimen is provided below (Table 22).
GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).
Table 22. Administration regimen of combination immunotherapy in patients after complete (R0) resection of distant melanoma metastases.
Nivolumab** (on the same day as ipilimumab**) | 1 mg/kg | IV infusion over 30 min | every 21 days | no more than 4 administrations in total |
|---|---|---|---|---|
Ipilimumab** (on the same day as nivolumab**) | 3 mg/kg | IV infusion over 30 minutes | every 21 days | no more than 4 administrations in total |
After completion of combination therapy, nivolumab** monotherapy | 3 mg/kg (but not exceeding 240 mg) or 240 mg | IV infusion over 30 minutes | every 14 days | up to 12 months from the start of adjuvant therapy |
480 mg | IV infusion over 30 minutes | every 21 days | up to 12 months from the start of adjuvant therapy |
3.4.11. Approaches to the treatment of metastatic and unresectable cutaneous melanoma (unresectable IIIC/D – IV) in individuals under 18 years of age
Introduction: therapy for metastatic and unresectable cutaneous melanoma in pediatric patients is insufficiently studied: due to the rarity of this disease in children, large randomized trials of modern antineoplastic drugs have not been conducted in this patient population. The working group for the development and revision of clinical guidelines recommends the participation of patients under 18 years of age in clinical trials. A number of drugs have been studied in small non-randomized trials, or there are individual clinical case reports of their use, which formed the basis for their inclusion in the clinical guidelines (see Table 23). If there are contraindications to the use of these drugs or if they are ineffective, alternative antineoplastic therapy (in accordance with recommendations for adult patients) may be prescribed by a medical panel for life-saving indications.
In pediatric patients with metastatic and unresectable cutaneous melanoma, it is recommended to administer systemic antitumor treatment, informing the patient (and/or their parents, legal representatives) about the potential benefits and limitations of this treatment method (see Table 23) [214,535-541].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
Comment: to date, responses to treatment have been reported with #ipilimumab** monotherapy, #nivolumab** monotherapy, and #dacarbazine** monotherapy. These drugs should be considered as first-line options.
Table 23. Antineoplastic drug therapy regimens in patients under 18 years of age with metastatic and unresectable melanoma (for all regimens LoR C, LoE 4).
Comment: #Pembrolizumab** (anti-PD1) was investigated in phase II (KEYNOTE-051 trial) [536]. The study included 155 patients aged 6 months to 17 years with melanoma or PD-L1+ solid tumors and lymphoma, including 8 patients (5%) with melanoma. No objective responses were registered among the 8 included patients. This may be due to the fact that 4 patients were 3 years of age or younger, which once again highlights the differences of melanoma in this age group from adolescent melanoma, which in its biological characteristics is close to adult cutaneous melanoma.
#Ipilimumab** (anti-CTLA4) has been studied in children aged 2–18 years and 12–18 years with metastatic or unresectable disease; 12 patients were included, #ipilimumab** 3 mg/kg (n = 4) and ipilimumab 10 mg/kg (n = 8). With a follow-up of more than one year, #ipilimumab** demonstrated results similar to those of therapy in adults. The incidence of grade 3 and 4 adverse events was 1 case at a dose of 3 mg/kg and 5 cases at a dose of 10 mg/kg, respectively [535, 537].
BRAF inhibitors have also not been well studied in children. A phase I study (BRIM-P) included 6 patients aged 12–17 years with metastatic BRAF-mutated melanoma. Two dosing regimens of #vemurafenib** 720 mg twice daily orally vs 960 mg twice daily orally were compared [214]. The investigators concluded that an effective and tolerable dose was not determined due to the small sample size of patients; no objective responses were registered [214]. However, positive results of combination targeted therapy in the treatment of children with BRAF-mutated glioma [542, 543] support the use of combination targeted therapy in pediatric patients with cutaneous melanoma harboring a BRAF mutation. This is especially true for adolescent cutaneous melanoma, which is most similar to adult cutaneous melanoma, although early-phase studies demonstrated the tolerability of #dabrafenib** in children under 12 years of age at a dose of 3.75–5.25 mg/kg/day [543].
Any other drugs that have proven effective in the treatment of adult melanoma patients can be used in pediatric practice only after a concilium at a federal center and by decision of a medical commission.
3.5 Anesthesia
The principles of analgesia and optimal selection of pain management therapy in patients with melanoma and chronic pain syndrome correspond to the analgesia principles outlined in the clinical guidelines "Chronic Pain Syndrome in Adult Patients in Need of Palliative Medical Care" [544].
3.6. Supportive care in patients with cutaneous melanoma
3.6.1. Principles for the prevention of acute and delayed nausea and vomiting during medical treatment
of cutaneous melanoma are outlined in the clinical guidelines "PRACTICAL GUIDELINES FOR THE PREVENTION AND TREATMENT OF NAUSEA AND VOMITING IN CANCER PATIENTS" [545].
3.6.2. Principles of treatment and prevention of bone complications
in patients with cutaneous melanoma are outlined in the clinical guidelines "USE OF BONE-MODIFYING AGENTS (BMAs) FOR THE PREVENTION AND TREATMENT OF BONE PATHOLOGY IN MALIGNANT NEOPLASMS" [546].
3.6.3. Principles for the prevention and treatment of immune-mediated adverse events
in patients with cutaneous melanoma correspond to the principles outlined in the guidelines PRACTICAL GUIDELINES FOR THE MANAGEMENT OF IMMUNE-MEDIATED ADVERSE EVENTS" [547].
3.6.4. Principles for the prevention and treatment of infectious complications and febrile neutropenia
in patients with cutaneous melanoma correspond to the principles outlined in the clinical guidelines "PRACTICAL GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF FEBRILE NEUTROPENIA" [548].
3.6.5. Principles for the prevention and treatment of hepatotoxicity
in patients with cutaneous melanoma correspond to the principles outlined in the clinical guidelines "CLINICAL GUIDELINES FOR THE CORRECTION OF ANTITUMOR THERAPY-INDUCED HEPATOTOXICITY" [549].
3.6.6. Principles for the prevention and treatment of cardiovascular complications
in patients with cutaneous melanoma correspond to the principles outlined in the clinical guidelines "PRACTICAL GUIDELINES FOR THE CORRECTION OF CARDIOVASCULAR TOXICITY OF ANTITUMOR DRUG THERAPY" [550].
3.6.7. Principles for the prevention and treatment of dermatological complications
in patients with cutaneous melanoma correspond to the principles outlined in the clinical guidelines "PRACTICAL GUIDELINES FOR THE DRUG TREATMENT OF DERMATOLOGICAL REACTIONS IN PATIENTS RECEIVING ANTITUMOR DRUG THERAPY" [551].
3.6.8. Principles of nutritional support
in patients with cutaneous melanoma correspond to the principles outlined in the clinical guidelines "PRACTICAL GUIDELINES FOR NUTRITIONAL SUPPORT IN CANCER PATIENTS" [552].
3.6.9. Principles for the prevention and treatment of thromboembolic complications
in patients with cutaneous melanoma correspond to the principles outlined in the clinical guidelines "PRACTICAL GUIDELINES FOR THE PREVENTION AND TREATMENT OF THROMBOEMBOLIC COMPLICATIONS IN CANCER PATIENTS" [553].
3.6.10. Principles for the prevention and treatment of nephrotoxicity
in patients with cutaneous melanoma correspond to the principles outlined in the clinical guidelines PRACTICAL GUIDELINES FOR THE CORRECTION OF NEPHROTOXICITY OF ANTITUMOR DRUGS" [554].
3.6.11. Principles for the prevention and treatment of drug extravasation sequelae
in patients with cutaneous melanoma correspond to the principles outlined in the clinical guidelines "RECOMMENDATIONS FOR THE MANAGEMENT OF THE CONSEQUENCES OF ANTITUMOR DRUG EXTRAVASATION" [555].
3.7 Medical Nutrition Therapy
To date, no reliable data have been obtained regarding the effect of dietary habits on the risk of developing cutaneous melanoma, melanoma of other sites, or on the risk of relapse or progression of this disease in individuals with an established diagnosis. There is conflicting evidence that a diet rich in vitamin D and carotenoids, as well as reduced alcohol consumption, may be associated with a reduced risk of developing melanoma. In this regard, it is not recommended to make any changes to the patients' usual diet unless dictated by the need to correct comorbid conditions or to relieve or prevent complications of ongoing treatment (surgical, drug, or radiation therapy) [556].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
4. Medical Rehabilitation and Sanatorium-Resort Treatment
Currently, for most types of medical rehabilitation, there are no clinical trials involving melanoma patients. These recommendations are based on the fact that numerous studies, including meta-analyses (Steffens, D et al. 2018, etc.) and systematic reviews (Nicole L. Stout et al., 2017 and R. Segal et al., 2017, etc.), have proven that various types of medical rehabilitation significantly accelerate functional recovery, shorten hospital stay after surgery, and reduce the incidence of complications and mortality in patients with other malignancies.
4.1. Pre-rehabilitation
It is recommended to perform prehabilitation in all patients with cutaneous melanoma to accelerate functional recovery, shorten postoperative hospital stay, and reduce the incidence of treatment-related complications and mortality. Prehabilitation includes physical training (exercise therapy), psychological and nutritional support, and patient education [557].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: it is recommended to advise the patient to increase physical activity 2 weeks before surgery to reduce hospital stay and the risk of postoperative complications, as well as to improve postoperative quality of life [558].
4.2. Rehabilitation Following Surgical Treatment
4.2.1. First stage of rehabilitation
It is recommended to use a multidisciplinary approach in the rehabilitation of adult patients in oncodermatology, incorporating exercise rehabilitation, psychological support, and occupational therapy [559].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
It is recommended to initiate rehabilitation early in adult patients, as it improves functional outcomes after surgery in oncodermatology [560].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
• It is recommended to develop an individualized exercise therapy program for each specific case, based on the characteristics and extent of surgery in children [561].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended to prescribe medical massage (excluding the operated anatomical area) to all patients in the early postoperative period, as medical massage increases muscle tone, improves postoperative wound healing, reduces pain and edema, and helps prevent thrombotic complications [562].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients use pneumatic compression to prevent postoperative edema [563].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients use kinesiotaping for the treatment and prevention of postoperative edema, which is comparable in effect to pressotherapy [563].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients combine positioning therapy, exercise therapy, cryotherapy to the surgical area, medical massage, and electrotherapy for pain relief [564].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients gradually expand the scope of exercise therapy. Once active abduction becomes possible, full weight-bearing on the operated limb is permitted [560].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
4.2.2. Second stage of rehabilitation
It is recommended that adult patients use techniques aimed at scar mobilization to prevent the formation of coarse scar changes, including in deep soft tissue layers: deep medical massage, stretching exercises, and ultrasound therapy to soften scar changes [565].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients with lymphedema undergo complete decongestive therapy, including manual lymphatic drainage (medical massage of the lower or upper extremity), wearing compression garments, a set of exercise therapy (physical therapy) exercises, and skin care [566].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients, in combination with complete decongestive therapy, use intermittent pneumatic compression lasting at least 1 h with a chamber pressure of 30–60 mm Hg [566].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients, in combination with complete decongestive therapy, use low-level laser therapy [567].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
4.2.3. Third stage of rehabilitation
It is recommended that adult patients perform and gradually expand a set of exercise therapy (physical therapy) exercises including aerobic exercise, which improves the outcomes of combined treatment for malignant neoplasms and quality of life [568].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients receive medical massage to improve quality of life, reduce pain syndrome, and fatigue [569].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
4.3. Rehabilitation During Chemotherapy
It is recommended that adult patients start physical activity early during chemotherapy, which helps prevent muscle weakness, hypotrophy, and decreased exercise tolerance [570].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients use aerobic exercise during chemotherapy, which increases hemoglobin and erythrocyte levels and reduces the duration of leukopenia and thrombocytopenia, as well as increases the likelihood of completing the planned chemotherapy course [571,572].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients perform exercise therapy (physical therapy) during chemotherapy, which helps reduce fatigue and depression. Combining exercise therapy with psychological support in treating fatigue and depression during chemotherapy is more effective than drug correction alone [573].
GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).
It is recommended that adult patients have the volume and intensity of exercise therapy (physical therapy) individually tailored during chemotherapy based on the degree of fatigue (mild, moderate, severe), and that the intensity of exercise therapy be increased as the general condition improves [570].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients combine aerobic and resistance exercise to manage treatment side effects and increase treatment tolerance [570].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients undergo a 6-week course of medical massage starting after the initiation of chemotherapy, which reduces fatigue during combined treatment [574].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients perform balance training exercises, which is more effective for correcting polyneuropathy than a combination of endurance and resistance exercises [575].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients be prescribed a 6-week walking course (terrain cure) for patients with skin or mucosal melanoma and chemotherapy-induced toxic polyneuropathy as part of a general rehabilitation program to control the clinical manifestations of polyneuropathy [576].
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
It is recommended that adult patients receive low-frequency magnetic therapy for the treatment of peripheral polyneuropathy during chemotherapy [577].
GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).
It is recommended that adult patients receive transcutaneous electrical nerve stimulation (TENS) for 20 minutes a day for 4 weeks to treat chemotherapy-induced polyneuropathy [578].
GCP CLEL 3Grade of Recommendation – C (Level of Evidence – 3).
It is recommended that adult patients use low-level laser therapy to prevent chemotherapy-induced oral mucositis [579].
GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).
It is recommended that adult patients use scalp cooling systems (devices for the prevention of alopecia during chemotherapy) to prevent alopecia during chemotherapy [580].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
4.4. Rehabilitation During Radiation Therapy
It is recommended that adult patients perform a set of exercise therapy (physical therapy) exercises (aerobic exercise combined with resistance training) during radiotherapy, which helps prevent fatigue and improves quality of life during radiotherapy [581].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients perform a set of exercise therapy (physical therapy) exercises, which increases bone mineral density and patient endurance during radiotherapy, primarily in patients with bone metastases [582].
GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).
It is recommended that adult patients, 3 days after the start of radiotherapy, begin low-level laser therapy for 3 days a week to prevent radiation dermatitis [583].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
4.5. Principles of psychological rehabilitation in patients with malignant skin neoplasms
It is recommended that adult patients be provided with information about the disease, mental reactions; areas of responsibility during the treatment process; methods of communication with relatives, medical staff; ways to obtain additional information about their disease or condition; and ways to obtain social support, which leads to improved quality of life and disease outcomes [584-586].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
It is recommended that adult patients achieve a combined effect of coping behavior and perceived social support, which leads to fewer intrusive and avoidant thoughts before treatment and ensures better psychological adaptation of the patient 1 month after treatment [587,588].
GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).
It is recommended that adult patients undergo psychoeducational interventions and psychological support (self-diagnosis of pathological mental reactions; coping strategies for stress; tracking the mutual influence of mental reactions and physical condition), which can be considered as the main mechanism for transforming stressful events into personal experience, contributing to social and mental adaptation in the context of disease and treatment [589,590].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).
Comment: the 3 most common coping styles found among melanoma patients in psycho-oncology research are:
active behavioral coping with emotional, physical, and social difficulties associated with the disease and treatment;
active cognitive coping, including attitudes, beliefs, and reflections about the disease;
avoidant coping, including attempts to actively avoid problems or indirectly reduce emotional distress through distraction.
Overall, studies show that patients who use active (problem-oriented) coping strategies demonstrate better adaptation to the disease than those who use passive or avoidant coping styles [591-594].
Patients who used active-behavioral coping methods reported higher levels of self-esteem and energy, fewer physical symptoms, and reduced irritability and asthenia [595,596].
In contrast, in patients with early-stage melanoma, a positive correlation was demonstrated between avoidant coping methods and anxiety, depression, confusion, and unstable mood background [591,595-597].
Boesen et al. demonstrated that structured interventions providing psychoeducational support contribute to a reduction in distress and mood disorders and lead to more active use of coping strategies among melanoma patients [598,599].
It is recommended that adult patients undergo targeted psychotherapeutic interventions for mental reactions associated with melanoma (asthenic-anxious-depressive reactions, narcissistic reactions, PTSD-related reactions, social isolation), which leads to a decrease in anxiety, health-related disorders, and positive changes in coping with the disease [600].
GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).
Comment: the results of psychotherapeutic interventions demonstrate a low level of depression, confusion, asthenia, apathy, and general mood lowering among melanoma patients [591]. Also, many studies demonstrate a positive effect of the intervention on immune system functions, including an increase in certain types of natural killer (NK) cells and an increase in the tumor-fighting potential of NK cells [596]. Over 5 years of follow-up, these researchers were able to show that psychological and biological changes, in turn, were associated with relapse and survival rates [595].
5. Prevention and Dispensary Observation
5.1. Prevention
To reduce the risk of primary melanoma as well as to prevent the occurrence of new melanomas or other malignant neoplasms of the skin, all people are recommended to avoid sunburn or exposure to artificial ultraviolet radiation [601-605].
GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).
5.2. Dispensary follow-up
Adults with oncological diseases included in ICD-10 categories C00-D09 are subject to dispensary observation (follow-up).
Dispensary observation is organized at the outpatient oncological care center, or in the primary oncological office of a medical organization, oncological dispensary (oncological hospital), or other medical organizations providing medical care to patients with oncological diseases.
Comments: 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 considered the early detection of disease recurrence (especially distant metastases), early detection of secondary tumors (in particular, new melanomas), as well as psychosocial support for patients.
To reduce the risk of primary melanoma as well as to prevent the development of new melanomas or other malignant skin neoplasms, it is recommended to avoid sunburn or exposure to artificial ultraviolet radiation [601-605].
GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).
All patients with a previously established diagnosis of cutaneous melanoma are recommended to perform regular self-examinations of the skin and peripheral lymph nodes and promptly consult a physician if any abnormalities are detected [606-608].
GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).
Table 21 presents the recommended follow-up schedule for a patient with a previously established diagnosis within the framework of clinical monitoring (dispensary observation), compiled on the basis of recommendations given in the "Diagnostics" section and the risks of disease progression.
Table 21. Follow-up schedule for patients with cutaneous melanoma.
1. Follow-up for patients with a very low risk of disease progression (stage 0–IA).
Recommended physical examinations with a thorough assessment of the skin and peripheral lymph nodes every 6 months for 3 years, then annually for 10 years of follow-up. Instrumental examinations are recommended only on indication — in accordance with the recommendations given in the subsection "Instrumental diagnostic procedures" [54,609].
GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).
2. Patients with a low risk of progression (stages IB–IIB).
Recommended physical examinations with a thorough assessment of the skin and peripheral lymph nodes every 6 months for 5 years, then annually for 10 years of follow-up, ultrasound of regional lymph nodes for 3 years [54,609].
GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).
3. Patients with a high risk of disease progression (stages IIC–III and stage IV after resection of solitary metastases).
Recommended physical examinations with a thorough assessment of the skin and peripheral lymph nodes every 3 months for 3 years, then every 6 months up to 10 years of follow-up; ultrasound of regional lymph nodes every 3 months for 3 years, then every 6 months up to 10 years of follow-up; diagnostic imaging (CT of the chest, CT or MRI of the abdominal cavity and pelvis with IV contrast, or whole-body 18F-FDG PET/CT) every 6 months up to 5 years of follow-up [126,127,610].
GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).
In patients with newly diagnosed distant metastases, it is recommended to perform brain MRI with IV contrast to rule out metastatic brain involvement [128,136-138,140].
GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).
It is recommended to provide family genetic counseling in familial atypical multiple mole-melanoma (FAMMM) syndrome, xeroderma pigmentosum, and neurocutaneous melanosis [611-617].
Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).
6. Organization of Medical Care
Medical care, with the exception of medical care within clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011, "On the Fundamentals of Protecting Public Health in the Russian Federation," is organized and provided:
in accordance with the regulations on the organization of medical care by types of medical care, which is approved by the authorized federal executive body;
in accordance with the procedures for the provision of medical care approved by the authorized federal executive body and mandatory for execution on the territory of the Russian Federation by all medical organizations;
based on these clinical guidelines;
taking into account the standards of medical care approved by the authorized federal executive body.
Primary specialized health care is provided by an oncologist and other medical specialists at an ambulatory cancer care center, or, in its absence, at a primary oncology office or the outpatient department of an oncological dispensary (cancer hospital).
In case of suspicion or detection of an oncological disease in a patient, general practitioners, district general practitioners, general family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the established manner for consultation to an outpatient oncological care center, or, in its absence, to a primary oncological office or the outpatient department of an oncological dispensary (oncological hospital) for the provision of primary specialized health care.
Consultation at an outpatient oncological care center, primary oncological office, or outpatient department of an oncological dispensary (oncological hospital) must be performed no later than 3 working days from the date of issuing the referral for consultation. The oncologist of the outpatient oncological care center (in the absence of such a center, the oncologist of the primary oncological office or outpatient department of the oncological dispensary/hospital) arranges for the acquisition of biopsy (surgical) material, as well as the performance of other diagnostic tests 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 includes the ambulatory cancer care center (primary oncology office), the patient is referred by the oncologist to an oncological dispensary (cancer hospital) or to a medical organization providing medical care to patients with oncological diseases.
The timeframe for performing pathological examinations necessary for the histological verification of malignant neoplasms shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material by the pathoanatomical bureau (department).
The timeframe for diagnostic instrumental and laboratory examinations in case of suspected oncological disease shall not exceed the timeframes established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation, which is 7 working days from the date of prescribing the examinations.
The diagnosis of an oncological disease is established by a medical specialist based on the results of diagnostic examinations, including cytological and/or histological verification of the diagnosis, except for cases where obtaining biopsy and/or puncture material is not feasible.
The oncologist (pediatric oncologist) of the outpatient oncological care center (primary oncological office) refers the patient to an oncological dispensary (oncological hospital) or another medical organization providing medical care to patients with oncological diseases, including those subordinate to a federal executive body (hereinafter referred to as the federal medical organization), to clarify the diagnosis (if it is impossible to establish the diagnosis, including the extent of the oncological process and the stage of the disease), determine treatment tactics, and in the presence of medical indications for specialized, including high-tech, medical care.
In complex clinical cases, to clarify the diagnosis (if it is impossible to establish the diagnosis, including the extent of the oncological process and the stage of the disease) for the purpose of evaluation, interpretation, and description of the results, the oncologist (pediatric oncologist) arranges the referral of:
digital images obtained from pathomorphological studies to a pathologo-anatomical bureau (department) of the fourth group (reference center) via information interaction, including the use of telemedical technologies for remote interaction between medical workers;
digital images obtained from radiation imaging results to the remote diagnostic consultation center for radiation diagnostics through information interaction, including via telemedicine technologies for remote interaction between medical workers;
biopsy (surgical) material for repeated pathomorphological, immunohistochemical, and molecular genetic studies: to the pathoanatomical bureau (department) of the fourth group (reference center), as well as to molecular genetic laboratories for molecular genetic testing.
Treatment tactics are determined by a medical board (consilium) consisting of oncologists, pediatric oncologists (for patients under 18 years of age), a radiation therapist, and a neurosurgeon (for nervous system tumors) of a medical organization that includes departments of surgical methods for treating malignant neoplasms, anti-tumor drug therapy, and radiotherapy (hereinafter referred to as the oncological consilium), including an oncological consilium held using telemedical technologies, involving other medical specialists if necessary.
Clinical follow-up (dispensary observation) by an oncologist (pediatric oncologist in the case of a patient under 18 years of age) for a patient with a detected oncological disease is established and carried out in accordance with the procedure for dispensary observation of adults with oncological diseases.
For accounting purposes, information about a newly diagnosed case of an oncological disease is sent within 3 working days by the oncologist of the medical organization where the corresponding diagnosis was established to the oncological dispensary or the organization of a constituent entity of the Russian Federation that performs the registration of patients with newly diagnosed malignant neoplasms, including through the use of the Unified State Health Information System. If the presence of an oncological disease is confirmed in a patient, information about the refined diagnosis is sent from the oncological dispensary or the organization of the constituent entity of the Russian Federation that performs the registration of patients with newly diagnosed malignant neoplasms to the medical organization providing clinical follow-up of the patient.
Specialized, including high-tech, medical care in medical organizations providing medical care to the adult population with oncological diseases is provided on the basis of medical indications stipulated by the regulations on the organization of specialized, including high-tech, medical care.
Specialized medical care, excluding high-tech medical care, in medical organizations subordinate to federal executive authorities is provided based on medical indications provided for in paragraph 5 of the procedure for referring patients to medical organizations and other organizations subordinate to federal executive authorities for the provision of specialized (excluding high-tech) medical care, provided for in the appendix to the regulations on organizing the provision of specialized, including high-tech, medical care. (Paragraph 5: to receive specialized medical care on a planned basis, the choice of a federal medical organization is carried out upon the referral of the attending physician.) If the Program involves several federal medical organizations providing specialized medical care for diseases, conditions (group of diseases, conditions) corresponding to the patient's diseases, conditions (group of diseases, conditions), the attending physician is obliged to inform the patient (the patient's legal representative) about the possibility of choosing a federal medical organization, including the potential waiting times for specialized medical care, which may exceed the waiting times established by the program of state guarantees of free medical care to citizens.
The waiting time for the provision of specialized (excluding high-tech) medical care must not exceed the timeframes established in the program of state guarantees of free medical care to citizens approved by the Government of the Russian Federation, which is 7 working days.
If a patient with an oncological disease has medical indications for medical rehabilitation, the oncologist arranges for it to be provided in accordance with the procedure for organizing adult medical rehabilitation.
If a patient with an oncological disease has medical indications for sanatorium-resort treatment, the oncologist arranges for it in accordance with the procedure for organizing sanatorium-resort treatment.
Palliative medical care for a patient with oncological diseases is provided in accordance with the provision on organizing the provision of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, public associations, and other non-profit organizations operating in the field of health protection.
If an oncological disease is suspected and/or detected in a patient during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine management tactics and the need for additional other methods of specialized antitumor treatment.
Indications for hospitalization in a medical organization in an emergency or urgent form are:
presence of oncological disease complications requiring emergency and urgent specialized medical care;
presence of complications from cancer treatment (surgical intervention, radiation therapy, drug therapy, etc.) requiring emergency and urgent specialized medical care.
Indications for planned hospitalization in a medical organization are:
need to perform complex interventional diagnostic medical procedures, as well as endoscopic examinations when they cannot be performed on an outpatient basis, requiring subsequent monitoring in a 24-hour or day hospital setting;
the presence of indications for specialized anti-tumor treatment (surgical intervention, radiation therapy—including contact, external beam, and other types of radiation therapy—drug therapy, etc.) requiring monitoring in an inpatient or day-inpatient setting.
Indications for discharging a patient from a medical organization are:
completion of a course of treatment or one of the stages of providing specialized, including high-tech, medical care in a 24-hour or day hospital setting, provided there are no treatment complications requiring drug correction and/or inpatient medical interventions;
refusal of the patient or their legal representative from specialized, including high-tech, medical care in a 24-hour or day hospital setting, established by a medical board of an oncological care organization;
in cases of non-compliance by the patient with prescriptions or internal regulations of the medical and prophylactic institution, provided this does not threaten the patient's life and the health of others;
need to transfer the patient to another medical organization in the relevant medical specialty.
The conclusion on the advisability of transferring a patient to a specialized medical organization is made after a preliminary consultation on the provided medical documents and/or a preliminary examination of the patient by specialist physicians of the medical organization to which the transfer is planned.
Indications for referring a patient to another medical organization:
implementation of clinical guidelines aims to maximize the quality of medical care provided to patients in various clinical situations. If a medical organization lacks the capability to perform the recommended scope of medical care (e.g., lack of sentinel lymph node biopsy capability), it is recommended to use the routing system to federal centers with appropriate equipment and personnel;
given the rarity of this pathology, all cases of cutaneous melanoma in children aged 17 years and younger are recommended to be referred for consultation, either in person or via telemedicine technologies, to obtain a second opinion on the lifetime pathomorphological diagnosis at a reference center;
all patients with congenital large and giant melanocytic nevi aged 17 years and younger are recommended to be referred for consultation, either in person or via telemedicine technologies, to a federal center to make a decision on individual tactics for further treatment or monitoring;
clinical guidelines cannot describe the full diversity of real-world clinical practice and cover only the most frequent and typical clinical situations. If a practicing physician or medical organization encounters a clinical situation not reflected in these clinical guidelines (atypical disease course, need to initiate anti-tumor therapy despite contraindications, progression during recommended treatments, etc.), it is recommended to use telemedicine consultations or routing to national medical research centers to clarify treatment tactics;
identification or exacerbation of a comorbid condition unrelated to the profile of the oncological institution that hinders this stage of treatment requires routing to specialized medical organizations.
7. Additional Information
Known prognostic factors for cutaneous melanoma that are recommended to be recorded are presented in Table 22.
Table 22. Prognostic factors in cutaneous melanoma (according to the 8th edition TNM classification) [359].
Factor category | Prognostic factors | ||
|---|---|---|---|
Tumor-associated | Patient-associated | Environment-associated | |
Required for assessment | Tumor thickness, mitotic index, ulceration, extent of metastatic disease | Lymphocytic infiltrate, regression | Use of medications, especially immunosuppressants |
Additional | Lymphovascular invasion, perineural spread | Localization of the primary tumor, family history, immunodeficiency, sex, age (women and younger patients have a more favorable prognosis) | History of sunburns, visiting tanning salons |
New and promising | Molecular: mutations, gene expression, proteomics, microRNA | Immunogenetics, other characteristics of the patient's immune response | |
Criteria for Evaluating the Quality of Medical Care
Criteria for assessing the quality of medical care are presented in Table 23.
Table 23. Criteria for assessing the quality of medical care.
No. | Quality criteria | Performance evaluation |
|---|---|---|
1. | Ultrasound of regional lymph nodes performed (at diagnosis for all stages) | Yes/No |
2. | Pelvic ultrasound and/or pelvic CT and/or pelvic MRI performed (at diagnosis for stages IIA–IV) | Yes/No |
3. | Chest X-ray and/or chest CT performed (at diagnosis for stages IIA–IV) | Yes/No |
4. | Abdominal ultrasound (comprehensive) and/or abdominal CT, and/or abdominal MRI performed (at diagnosis for stages IIB–IV) | Yes/No |
5. | Surgical margin of at least 1 cm and no more than 2 cm performed for primary invasive cutaneous melanoma (during surgical intervention) | Yes/No |
6. | Recommendation given for sentinel lymph node biopsy in patients with Breslow cutaneous melanoma thickness greater than 0.8 mm | Yes/No |
7. | Chemotherapy and/or immunotherapy, and/or targeted therapy and/or radiation therapy performed upon morphological verification of the diagnosis (if indications for chemotherapy and/or immunotherapy and/or targeted therapy, and/or radiation therapy are present) | Yes/No |
8. | Dosimetric verification of the calculated plan performed (in radiation therapy) | Yes/No |
9. | Brain MRI with intravenous contrast performed in newly diagnosed stage IV no later than 30 days from the moment of diagnosing metastatic melanoma (in the absence of medical contraindications) | Yes/No |
10. | Morphological verification of the diagnosis performed before starting treatment, except for cases with an overt clinical picture of skin tumors and emergency surgery cases | Yes/No |
11. | Assessment of progression risk performed in patients with stage I–III disease in accordance with the AJCC/UICC TNM 8 classification | Yes/No |
12. | Prescription issued for molecular genetic testing for mutations in the BRAF gene in biopsy material (in case of a negative result, molecular genetic testing for mutations in the KIT gene in biopsy (surgical) material) in metastatic disease (stage III and IV or equivalent), if testing was not previously performed | Yes/No |
13. | Recommendations given for adjuvant therapy in patients after surgical treatment for high-risk cutaneous melanoma in accordance with these guidelines | Yes/No |
14. | Presence of a consultation with an oncologist, neurosurgeon, and/or radiation therapist in a patient with metastatic brain involvement | Yes/No |
15. | Presence of prescriptions for therapy with PD1 and/or CTLA4 monoclonal antibody blockers, BRAF inhibitors, or BRAF inhibitors in combination with MEK inhibitors in the absence of contraindications in patients with metastatic or unresectable melanoma with a V600 mutation in the BRAF gene in accordance with these guidelines | Yes/No |
16. | Presence of prescriptions for therapy with PD1 and/or CTLA4 monoclonal antibody blockers in the absence of contraindications in patients with metastatic or unresectable melanoma without a V600 mutation in the BRAF gene | Yes/No |
17. | Pathological examination of biopsy or surgical material performed with indication of the primary tumor Breslow thickness, presence or absence of ulceration, and assessment of the distance from all (lateral and deep) resection margins to the closest tumor edge (in patients who underwent surgical treatment for primary cutaneous melanoma) | Yes/No |
18. | Pathological examination of biopsy or surgical material performed with indication of the number of removed lymph nodes, the number of lymph nodes with metastatic involvement, and the nature of metastatic node involvement (conglomerates, capsule invasion) (in patients who underwent regional lymphadenectomy) | Yes/No |
19. | Performance of pathological examination of biopsy or surgical material using hematoxylin and eosin staining and immunohistochemical examination (in the absence of tumor signs at the light microscopy level) of the sentinel lymph node(s), indicating the number of removed lymph nodes, the number of lymph nodes with metastatic involvement, and the nature of metastasis involvement (sizing of micrometastases if detected) (in patients who underwent surgical treatment in the scope of sentinel lymph node biopsy) | Yes/No |
20. | Initiation of the 1st cycle of systemic antineoplastic treatment (targeted therapy, immunotherapy, chemotherapy) no later than the 30th day from the detection of metastatic disease (in the absence of contraindications) | Yes/No |
21. | Performance of the 1st cycle of adjuvant therapy no later than 12 weeks after surgical treatment (in patients indicated for adjuvant therapy, provided there are no postoperative complications and no contraindications) | Yes/No |
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Appendix A1. Working Group Composition
Working Group Moderator:
1. Samoylenko I.V., Cand. Sc. (Med.), Senior Researcher, Department of Skin Tumors, Department of Drug Treatment, National Medical Research Center of Oncology named after N.N. Blokhin, Russian Ministry of Health; Board Member of the Association of Melanoma Specialists.
Working Group
2. Banov S.M., D. Sc. (Med.), Leading Researcher, Department of Radiology and Radiosurgery, National Medical Research Center of Neurosurgery named after Academician N.N. Burdenko, Russian Ministry of Health.
3. Belysheva T.S., D. Sc. (Med.), Leading Researcher, Scientific and Consultative Department, Research Institute of Pediatric Oncology and Hematology, National Medical Research Center of Oncology named after N.N. Blokhin, Russian Ministry of Health.
4. Demidov L.V., D. Sc. (Med.), Professor, Head of the Department of Skin Tumors, Department of Drug Treatment, National Medical Research Center of Oncology named after N.N. Blokhin, Russian Ministry of Health, Chairman of the Board of the Association of Melanoma Specialists.
5. Zaretsky A.R., Head of the Laboratory of Molecular Oncogenetics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Head of the Oncology Division of the Prof. E.I. Schwartz Association of Specialists in Molecular Medicine, Laboratory and Clinical Genetics.
6. Zinovyev G.V., PhD, Head of the Department of Skin, Bone and Soft Tissue Tumors, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.
7. Novik A.V., MD, Senior Researcher, Research Department of Oncoimmunology, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Board Member of the Association of Melanoma Specialists.
8. Orlova K.V., PhD, Senior Researcher, Department of Skin Tumors, Drug Treatment Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health; Board Member of the Association of Melanoma Specialists.
9. Stroyakovsky D.L., PhD, Head of the Chemotherapy Department, Moscow City Oncology Hospital No. 62, Board Member of the Russian Society of Clinical Oncology.
10. Trofimova O.P., MD, Leading Researcher, Radiological Department, Radiation Oncology Division, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.
11. Fedenko A.A., MD, Head of the Drug Treatment of Tumors Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
12. Kharkevich G.Y., PhD, Leading Researcher, Department of Skin Tumors, Drug Treatment Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health; Board Member of the Association of Melanoma Specialists.
13. Yurchenkov A.N., PhD, Oncologist, Chemotherapy Department, Moscow City Oncology Hospital No. 62.
Mucosal Melanoma Section:
1. Alieva S.B., MD, Leading Researcher, Radiological Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.
2. Alymov Y.V., PhD, Oncologist, Head and Neck Tumors Surgical Department No. 11, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Executive Director of the All-Russian Public Organization "Russian Society of Head and Neck Oncologists".
3. Gordeev S.S., MD, Associate Professor, Department of Oncology, Radiology and Radiotherapy, Tyumen State Medical University, Head of the Research Planning and Coordination Division, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Executive Director of the Russian Society of Colorectal Cancer Specialists.
Early Diagnosis Section:
1. Garanina O.E., PhD, Assistant Professor, Department of Skin and Venereal Diseases, Privolzhsky Research Medical University of the Ministry of Health of the Russian Federation.
2. Kubanov A.A., MD, Professor, Academician of the RAS, President of the Russian Society of Dermatovenerologists and Cosmetologists (RODVK), Director of the State Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health.
3. Dubensky V.V., PhD, Professor, Department of Dermatovenereology with a Course of Dermatovenereology and Cosmetology of the Faculty of Additional Professional Education, Internships and Residency, Tver State Medical University of the Russian Ministry of Health.
4. Mordovtseva V.V., MD, Professor, Department of Skin and Venereal Diseases with a Course of Cosmetology, Moscow State University of Food Production.
5. Shlivko I.L., MD, Head of the Department of Skin and Venereal Diseases, Privolzhsky Research Medical University of the Ministry of Health of the Russian Federation.
Medical Rehabilitation Section:
1. Semiglazova T.Y., MD, Leading Researcher, Research Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Professor of the Department of Oncology, I.I. Mechnikov North-Western State Medical University of the Russian Ministry of Health.
2. Filonenko E.V., MD, Professor, 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, Oncologist.
Healthcare Organization Section:
1. Varfolomeeva S.R., MD, Professor, Deputy Director of N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Director of the Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology, Executive Director of the National Society of Pediatric Hematologists and Oncologists.
2. Ivanov S.A., MD, Professor, Corresponding Member of the RAS, Honored Doctor of the RF, Director of A.F. Tsyb Medical Radiological Research Center — branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Chief Freelance Oncologist of the Central Federal District of the Russian Ministry of Health.
3. Fomenko Y.A., PhD, Deputy General Director for Clinical and Expert Work, National Medical Research Center of Oncology of the Russian Ministry of Health.
4. Khaylova Z.V., PhD, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
5. Gevorkyan T.G., Deputy Director for Implementation of Federal Projects, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.
6. Komarov Y.I., PhD, Deputy Director for Organizational and Methodological Work, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.
Supportive Care Section
1. Gladkov O.A., Professor, MD, Director of EVIMED Medical Center LLC.
2. Karaseva V.V., MD, Associate Professor, Professor, Department of Oncology, Institute of Continuing Professional Education, Pirogov Russian National Research Medical University of the Russian Ministry of Health.
No conflicts of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
oncologists;
surgeons;
radiologists;
medical geneticists;
dermatovenerologists;
pathologists;
general practitioners (internal medicine);
district general practitioners;
general practitioners (family doctors);
medical students, residents, and graduate students.
pediatric oncologists;
pediatric surgeons;
pediatricians;
Grading system for levels of evidence for diagnostic methods (diagnostic interventions)
Level of evidence | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized clinical trials with meta-analysis |
2 | Individual studies with reference-method control, or individual randomized controlled trials and systematic reviews of studies of any design except randomized controlled trials incorporating meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Grading system for levels of evidence for prevention, treatment and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)
Level of evidence | Definition |
|---|---|
1 | Systematic review of randomized controlled trials with meta-analysis |
2 | Individual randomized controlled trials and systematic reviews of studies of any design, excluding randomized controlled trials, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Grades of Recommendation Scale for Prevention, Diagnostic, Treatment, and Rehabilitation Methods (Preventive, Diagnostic, Therapeutic, Rehabilitation Interventions)
Grade of Recommendation | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines
The guideline updating mechanism provides for their systematic revision at least once every 3 years, as well as upon the emergence of new evidence-based data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, 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
These clinical guidelines have been developed taking into account the following regulatory and legal documents:
1. Order of the Russian Ministry of Health No. 116n dated February 19, 2021, "On Approval of the Procedure for Providing Medical Care to Adult Patients with Oncological Diseases".
2. Order of the Russian Ministry of Health No. 548n dated June 4, 2020, "On Approval of the Procedure for Dispensary Observation of Adults with Oncological Diseases".
3. Order of the Russian Ministry of Health No. 404n dated April 27, 2021, "On Approval of the Procedure for Preventive Medical Examination and General Clinical Health Screening (Dispensary Profiling) of Certain Groups of the Adult Population".
4. Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care".
5. Order of the Russian Ministry of Health No. 194n dated March 11, 2021, "On Approval of Standards of Medical Care for Adults with Cutaneous and Mucosal Melanoma".
6. Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019, "On Approval of the List of Vital and Essential Drugs, as Well as Lists of Drugs for Medical Use and the Minimum Assortment of Drugs Required for Medical Care".
7. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On Approval of the Procedure and Timeframes for the Development of Clinical Guidelines, Their Revision, Standard Template of Clinical Guidelines, and Requirements for Their Structure, Composition and Scientific Validity of Information Included in Clinical Guidelines" (registered with the Ministry of Justice of Russia on May 8, 2019, No. 54588).
8. Methodological Recommendations for Assessing the Scientific Validity of Information Included in Clinical Guidelines, Center for Expertise and Quality Control of Medical Care of the Ministry of Health of the Russian Federation, 2019.
9. Current instructions for the medicinal products mentioned in these clinical guidelines can be found at http://grls.rosminzdrav.ru.
10. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services".
Table A3-1. Terms describing procedures in the clinical guidelines and possible (closest) terms from the current nomenclature of medical services.
Term appearing in the clinical guideline | Types and subtypes of medical services most suitable for the clinical guideline term (based on the nomenclature of medical services approved by Order No. 804n of the Russian Ministry of Health dated October 13, 2017) |
|---|---|
Dermoscopy | A03.01.001 Examination of the skin under magnification (dermoscopy) A03.01.001.001 Confocal reflectance microscopy of the skin |
Digital dermoscopic imaging | A03.01.001 Examination of the skin under magnification (dermoscopy) A03.01.001.001 Confocal reflectance microscopy of the skin |
In vivo pathomorphological examination of biopsy material | A10.30.001 Macroscopic examination of removed surgical specimen A08.01.001 Pathological examination of skin biopsy (surgical) material; A08.01.001.002 Pathological examination of skin biopsy (surgical) material using immunohistochemical methods |
Cytological examination of tumor material | A08.01.002 Cytological examination of skin micropreparation |
Ultrasound examination of regional lymph nodes | A04.06.002 Ultrasound examination of lymph nodes (one anatomical region) |
Computed tomography (CT) with intravenous contrast of the affected anatomical region | A06.08.007.004 Computed tomography of paranasal sinuses with intravenous bolus contrast enhancement A06.08.009.002 Computed tomography of the neck with intravenous bolus contrast enhancement A06.09.005.002 Computed tomography of thoracic organs with intravenous bolus contrast enhancement A06.30.005.002 Computed tomography of abdominal and retroperitoneal organs with intravenous bolus contrast enhancement A06.20.002.003 Computed tomography of pelvic organs in women with contrast enhancement A06.21.003.003 Computed tomography of pelvic organs in men with contrast enhancement A06.23.004.002 Computed tomography of soft tissues of the head with contrast enhancement A06.23.004.006 Computed tomography of the brain with intravenous contrast enhancement A06.12.050 Computed tomographic angiography of a single anatomical region |
Magnetic resonance imaging (MRI) with intravenous contrast of the affected anatomical region | A05.01.002 Magnetic resonance imaging of soft tissues A05.01.002.001 Magnetic resonance imaging of soft tissues with contrast enhancement A05.03.004 Magnetic resonance imaging of the facial skull A05.03.004.001 Magnetic resonance imaging of the facial skull with intravenous contrast enhancement |
Cytological examination of a scraping or touch smear | A11.01.016 Obtaining a touch smear from the skin surface A11.01.009 Skin scraping A11.01.001 Skin biopsy A11.01.005 Biopsy of nodules, tophi |
Incisional (punch) full-thickness skin biopsy | A11.01.001 Skin biopsy A11.30.013 Biopsy of soft tissue tumors and tumor-like lesions A11.30.014 Core needle biopsy of superficial tumors and lymph nodes under visual control |
Planar resection (of a skin neoplasm) | A11.01.001 Skin biopsy |
Metastasis biopsy under ultrasound/CT guidance | A11.06.001.001 Ultrasound-guided lymph node puncture A11.06.002.001 Ultrasound-guided lymph node biopsy A11.30.024.001 Ultrasound-guided soft tissue puncture A04.30.009 Ultrasound navigation for minimally invasive procedures A11.03.001.002 Computed tomography-guided core needle biopsy of the spine A11.03.001.003 Computed tomography-guided core needle biopsy of pelvic bones A11.09.003.002 Ultrasound-guided pleural puncture A11.14.001.001 Ultrasound-guided liver biopsy A11.15.001.001 Ultrasound-guided puncture biopsy of the pancreas |
Laser surgery using a CO2 laser | A22.01.003 Laser destruction of skin tissue A22.30.013 Laser surgery for soft tissue neoplasms |
Eyelid skin plastic surgery | A16.26.111 Eyelid repair (blepharoplasty) with and without tissue grafting A16.26.111.001 Upper eyelid repair without tissue grafting via percutaneous approach A16.26.111.002 Upper eyelid repair without tissue grafting via transconjunctival approach A16.26.111.003 Lower eyelid repair via percutaneous subciliary approach with skin flap formation A16.26.111.004 Lower eyelid repair via percutaneous subciliary approach with myocutaneous flap A16.26.111.005 Lower eyelid repair via percutaneous subciliary approach with myopexy A16.26.111.006 Lower eyelid repair via percutaneous subciliary approach with canthopexy A16.26.111.007 Lower eyelid repair via percutaneous subciliary approach with transposition of orbital fat into the tear trough A16.26.111.008 Lower eyelid repair via transconjunctival approach A16.26.111.009 Biplanar lower eyelid repair A16.26.111.010 Asian blepharoplasty |
Photodynamic therapy | A22.01.007 Photodynamic therapy for diseases of the skin, subcutaneous adipose tissue, and skin appendages A22.01.007.001 Intraoperative photodynamic therapy for neoplasms of the skin, subcutaneous tissue, and skin appendages A22.30.020 Photodynamic therapy of a malignant neoplasm |
Medical genetic counseling | B01.006.001 Initial consultation (examination, interview) with a geneticist B01.006.002 Follow-up consultation (examination, interview) with a geneticist A01.30.013 Anamnesis and complaint collection during genetic counseling A01.30.014 Visual examination during genetic counseling A01.30.015 Pedigree construction |
Reconstructive and plastic surgical techniques | A16.01.005.005 Wide excision of a skin neoplasm with a reconstructive-plastic component A16.30.032.002 Excision of soft tissue neoplasms with a reconstructive-plastic component A16.30.075 Reconstructive and plastic surgeries with tissue complex transposition (skin, muscles, tendons) A16.30.058 Soft tissue plastic surgery A16.01.010 Autologous skin grafting A16.01.010.001 Skin grafting for wound closure using dermato-expansion A16.01.010.002 Local tissue flap repair of wound A16.01.010.004 Cross-finger skin flap A16.01.010.005 Free skin graft using a dermatome-perforated flap A16.09.032.005 Reconstructive and plastic surgeries on the chest wall and diaphragm for chest wall tumors (soft tissue, ribs, sternum, clavicle) A16.23.048.001 Microsurgical removal of a craniofacial neoplasm with skull base defect repair using autografts or artificial implants A16.23.048.002 Microsurgical removal of a craniofacial neoplasm using endoscopic techniques with skull base defect repair using autografts or artificial implants A16.23.049.001 Resection of the craniofacial complex with microsurgical reconstruction using autografts or artificial implants A16.23.049.002 Resection of the craniofacial complex with a reconstructive-plastic component A16.23.049.003 Resection of the craniofacial complex with microsurgical reconstruction A16.23.049.004 Resection of the craniofacial complex with microsurgical reconstruction using video-endoscopic technologies A16.23.050 Reconstructive surgeries for craniofacial neoplasms A16.23.050.001 Microsurgical reconstruction of the craniofacial complex with microsurgical reconstruction using autografts or artificial implants |
Excision (or re-excision, or removal, or repeat removal, or excision, or repeat excision) of a skin tumor with intraoperative morphological control of all resection margins | A16.01.005.005 Wide excision of a skin neoplasm with a reconstructive-plastic component + A08.30.017 Urgent intraoperative pathological examination |
Cryodestruction of skin tumors (or cryosurgery for skin tumors) | A24.01.004 Cryodestruction of skin |
Close-range X-ray therapy | A06.01.007 X-ray therapy for skin neoplasms A06.01.007.001 Close-range X-ray therapy for skin neoplasms |
Gamma therapy | A07.01.004 Telecobalt therapy for skin neoplasms |
Electron therapy | A07.30.025.001 External beam radiation therapy for soft tissue lesions using medical electron accelerators |
Brachytherapy | A07.30.014 Interstitial radiation therapy A07.30.028 Placement of endostat(s) during interstitial radiation therapy A07.30.007 Applicator radiation therapy with the fabrication and application of custom applicators. 3D-4D planning |
External beam radiation therapy with electron or photon beam | A07.30.025 External beam radiation therapy for soft tissue lesions |
Hypofractionated radiation therapy | A07.30.025 External beam radiation therapy for soft tissue lesions |
Regional lymphadenectomy, complete regional lymphadenectomy, or lymphadenectomy | A16.06.006 Cervical lymphadenectomy A16.06.006.001 Axillary lymphadenectomy A16.06.006.002 Extended cervical lymphadenectomy A16.06.006.003 Extended cervical lymphadenectomy with angioplasty A16.06.006.004 Extended cervical lymphadenectomy with a reconstructive-plastic component A16.06.006.003 Extended cervical lymphadenectomy with angioplasty A16.06.006.004 Extended cervical lymphadenectomy with a reconstructive-plastic component A16.06.016.003 Ilio-inguinal-femoral lymphadenectomy (Duquenois operation) A16.06.016.004 Bilateral ilio-inguinal-femoral lymphadenectomy (Duquenois operation) A16.06.014 Inguinal lymphadenectomy A16.06.014.001 Bilateral inguinal lymphadenectomy A16.06.014.002 Inguino-femoral lymphadenectomy A16.06.014.003 Bilateral inguino-femoral lymphadenectomy A16.06.015 Femoral lymphadenectomy A16.06.016 Iliac lymphadenectomy A16.06.016.001 Unilateral iliac lymphadenectomy A16.06.016.002 Bilateral iliac lymphadenectomy |
Massage | A21.01.001 General medical massage A21.01.009 Medical lower extremity massage |
Pneumatic compression | A15.12.002.001 Intermittent pneumatic compression of lower extremities A17.30.009 Barotherapy - extremity pressotherapy, pneumatic compression B05.027.001 Medical rehabilitation services for a patient after cancer surgery B05.027.002 Medical rehabilitation services for a patient after chemotherapy B05.027.003 Medical rehabilitation services for a patient after radiation therapy |
Kinesio taping, electrotherapy, laser therapy, low-level laser therapy, magnetotherapy | B05.027.001 Medical rehabilitation services for a patient after oncological surgery B05.027.002 Medical rehabilitation services for a patient after chemotherapy B05.027.003 Medical rehabilitation services for a patient after radiation therapy for a disease |
Percutaneous electrical stimulation | A17.24.010 Multifunctional neuromuscular electrical stimulation A17.30.006 Transcutaneous electrical nerve stimulation (TENS) |
Appendix B. Physician Action Algorithms
Fig. 1. Diagnostic and treatment algorithm for patients with cutaneous melanoma in local (0–III) stages of the disease.
Fig. 2. Diagnostic and treatment algorithm for patients with metastatic or unresectable cutaneous melanoma and a BRAF gene mutation.
Fig. 3. Diagnostic and treatment algorithm for patients with metastatic or unresectable cutaneous melanoma and a KIT gene mutation.
Fig. 4. Diagnostic and treatment algorithm for patients with metastatic or unresectable cutaneous melanoma without BRAF and KIT gene mutations.
Appendix C. Patient Information
Guidelines for self-skin examination and primary prevention of melanoma
The main risk factor for the development of melanoma and other skin tumors is ultraviolet damage, which occurs due to natural causes (sunburns) 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. Being outdoors poses no danger. |
3–7 | Protection required. Stay in the shade during midday hours. Wear long-sleeved clothing and a hat. Use sunscreen. |
8 | Extra protection required. Stay indoors during midday hours. Remain in the shade when outdoors. Be sure to wear long-sleeved clothing, a hat, and use sunscreen. |
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 corresponding to that indicated on the sunscreen label is achieved when it is applied to the skin in an amount of 2 mg/cm2; using a smaller amount sharply reduces the degree of skin protection against ultraviolet radiation. To understand the amount of sunscreen necessary for the skin protection claimed by the label, i.e., 2 mg/cm2, the "teaspoon rule" has been developed [618]:
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 amount 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:
It is recommended to periodically (at least once every 3–6 months) perform a self-examination of your entire skin using both a full-length and a hand-held mirror. The examination algorithm is shown schematically in Fig. 5;
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. 5. Skin examination algorithm.
Recommendations for chemotherapy complications
In case of chemotherapy complications, it is necessary to contact an oncologist (chemotherapist).
1. If body temperature rises to +38°C or higher, start taking antibiotics as prescribed by your oncologist.
2. In case of stomatitis:
diet with mechanical and thermal sparing of the mucosa;
frequently (every hour) rinse the oral cavity with decoctions of chamomile, oak bark, sage, and lubricate the gums with sea buckthorn (peach) oil;
treat the oral cavity as recommended by the oncologist.
3. In case of diarrhea:
diet – exclude fatty, spicy, smoked, sweet, dairy products, and fiber. Lean meat, 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.
Information for patients receiving therapy with monoclonal antibodies blocking CTLA4 and/or PD1.
Timely communication with your attending physician and nurse regarding your health status is an important part of helping the medical team protect you as safely as possible during treatment.
It is very important that any symptoms (side effects) associated with CTLA4 and/or PD1 blocker therapy are identified and treated at the very beginning of their manifestation; this will help prevent them from progressing 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 are the result of high immune system activity. Such side effects are called immune-mediated and differ from the side effects you may observe with other types of cancer treatment.
Side effects that you may experience usually occur within the first 12 weeks of treatment, but can also appear later.
It is very important that you inform your attending physician of any symptoms that appear during treatment with CTLA4 and/or PD1 blockers. Recognizing side effects in the early stages enables your attending physician to immediately initiate appropriate therapy and prevent side effects from progressing to more severe grades.
If, after treatment with CTLA4 and/or PD1 blockers, you experience any of the symptoms listed below, please inform your attending physician immediately.
Possible side effects after therapy with CTLA4 and/or PD1 blockers:
increased frequency of bowel movements to 2 or more per day or any nocturnal diarrhea, any stool containing mucus and blood;
abdominal pain or chills, as well as pain requiring medical intervention;
red, painful eyes or yellowish coloration of the whites of the eyes, blurred vision, inflammation or swelling of the eyes;
yellow coloration or redness of the skin, itchy rash, skin sensitivity to sunlight;
newly onset cough or shortness of breath;
fatigue or drowsiness;
difficulty concentrating or confusion;
headache, body aches, or pain at the tumor site;
fever (increase in body temperature up to +38° C);
sudden decrease or increase in body weight;
newly onset erectile dysfunction or loss of interest in intimate life.
Please pay special attention to any changes in your bowel habits. Keep a daily record of the number of bowel movements. If you have diarrhea, try to describe it using one of the terms below and determine the urgency level for your specific case:
loose stool;
watery;
painful;
bloody;
mucoid.
Diarrhea may not always present as loose stool. An increased frequency of bowel movements per day, even with hard stool, can potentially indicate a problem.
Important: side effects may occur anywhere from 1 week to several months after starting treatment with CTLA4 and/or PD1 blockers. If you experience any of the above symptoms, immediately inform your attending physician or nurse.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Appendix G1. WHO/ECOG Performance Status Scale [404]
Russian name: WHO/ECOG performance status scale.
Original title: The Eastern Cooperative Oncology Group/World Health Organization Performance Status (ECOG/WHO PS).
Source (official developer website, validation publication): https://ecog-acrin.org/resources/ecog-performance-status
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982, 5(6):649-655.
Type: rating scale.
Purpose: to describe the patient's level of functioning in terms of their ability to care for themselves, daily activities, and physical abilities (walking, work, etc.).
Content:
Score | Description |
|---|---|
0 | Fully active, able to carry on all pre-disease performance without restriction (90–100% on the Karnofsky scale) |
1 | Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work, 70–80% on the Karnofsky scale) |
2 | Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours (50–60% on the Karnofsky scale) |
3 | The patient is capable of only limited self-care, confined to a chair or bed for more than 50% of waking hours (30–40% on the Karnofsky scale) |
4 | Disabled, completely incapable of self-care, confined to a wheelchair or bed (10–20% on the Karnofsky scale) |
5 | Dead |
Scoring key (interpretation): provided within the scale itself.
Appendix G2. Karnofsky Performance Scale [619]
Russian name: Karnofsky scale.
Original title (if available): KARNOFSKY PERFORMANCE STATUS.
Source (official developer website, validation publication): Karnofsky DA, Burchenal JH: The clinical evaluation of chemotherapeutic agents in cancer. In: Evaluation of chemotherapeutic agents. edn. Edited by MacLeod C. New York: Columbia University Press; 1949: 191-205.
Type: rating scale.
Purpose: to describe the patient's level of functioning in terms of their ability to care for themselves, daily activities, and physical abilities (walking, work, etc.).
Content (template):
Karnofsky Performance Scale |
|---|
100 — Normal activity, no complaints 90 — Able to carry on normal activity; minor symptoms or signs of disease |
80 — Normal activity with effort; some minor symptoms or signs of disease 70 — Cares for self, unable to carry on normal activity or to do active work |
60 — Requires occasional assistance, but is able to care for most of his personal needs 50 — Requires considerable assistance and frequent medical care |
40 — Disabled, requires special care and medical assistance 30 — Severely disabled, hospitalization indicated, death not immediately imminent |
20 — Severely ill. Hospitalization and active treatment required 10 — Moribund |
0 — Death |
Key (interpretation): provided within the scale itself
Appendix G3. Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Russian title: Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Original title (if applicable): Response evaluation criteria in solid tumors 1.1.
Source (official developer website, validation publication):
Original publication: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45(2):228-247.
Type: rating scale.
Purpose: evaluation of response to chemotherapy.
The content, key, and template in Russian are presented in methodological guidelines No. 46 of the Scientific and Practical Center for Medical Radiology of the Moscow Healthcare Department [620].
Content:
1. Scope: Although this guideline may be applicable to studies of malignant brain tumors, separate criteria for evaluating treatment response have also been published for this nosological category. This document is not intended for use in studies concerning malignant lymphomas, as separate international guidelines have been published for assessing response in lymphomas.
2. It should also be noted that in routine clinical practice, oncologists frequently monitor malignant disease in patients through a series of imaging studies and make decisions to continue therapy based on both objective data and clinical symptoms. The RECIST guideline is not intended as a mandatory tool to support such decisions, except when the attending physician deems its use appropriate.
3. Evaluation of measurability of the tumor process prior to initiation of medical treatment.
3.1. Definitions
At baseline (prior to the initiation of therapy), tumor lesions and/or lymph nodes are classified as measurable or non-measurable according to the following criteria:
3.1.1. Measurable lesions
Tumor lesions: must be accurately measurable in at least one dimension (the largest diameter in the measurement plane must be recorded), with a minimum size of:
10 mm by CT scan (with slice thickness no greater than 5 mm);
10 mm by caliper measurement during clinical examination (if precise measurement is impossible, the lesion is considered non-measurable);
20 mm by chest X-ray.
Metastatically altered lymph nodes: considered pathologically enlarged and measurable if their short axis is 15 mm or more (based on CT with a slice thickness of no more than 5 mm). Both at baseline and during follow-up, only the short axis of the node should be measured and tracked.
3.1.2. Non-measurable lesions
These include:
Lesions with a maximum diameter of less than 10 mm;
Lymph nodes with a short axis of 10 to < 15 mm;
Lesions that cannot be objectively measured, including:
leptomeningeal carcinomatosis;
ascites;
pleural or pericardial effusion;
inflammatory breast cancer;
lymphangitis of the lung or skin;
abdominal masses or hepato-/splenomegaly detected on physical examination but not amenable to reproducible imaging measurement.
3.1.3. Special considerations for lesion measurability
3.1.3.1. Bone lesions:
Osteoscintigraphy, PET, or conventional X-rays are not considered adequate imaging modalities for measuring bone lesions. However, they may be used to confirm the presence or disappearance of bone lesions.
Lytic or mixed lytic-blastic lesions with measurable soft tissue components that can be assessed by CT or MRI may be considered measurable if they meet the measurability criteria outlined above.
Blastic bone lesions are considered non-measurable.
3.1.3.2. Cystic lesions:
Foci corresponding to the features of simple cysts on imaging should not be regarded as malignant and, accordingly, are not subject to classification as either measurable or non-measurable.
So-called "cystic lesions," presumed to be cystic metastases, may be considered measurable if they meet the established criteria. However, if non-cystic lesions are also present, these should be preferred when selecting target lesions.
3.1.3.3. Lesions after local treatment:
Tumor lesions located in previously irradiated areas or regions subjected to other locoregional treatment are generally not considered measurable unless documented progression is demonstrated in these lesions.
3.2. Specifications for measurement methods
3.2.1. Measurement of lesions
All measurements must be recorded in metric units, preferably using a caliper for clinical evaluation.
Baseline assessment should be performed as close to the start of therapy as possible, but no later than 4 weeks before treatment initiation.
3.2.2. Method of assessment
The same imaging method and identical technique should be used at all stages — both at baseline and during subsequent follow-ups.
Assessment using imaging methods is preferred unless the lesion cannot be visualized but is accessible for objective clinical evaluation.
Clinically detected lesions: considered measurable only if they are superficial and $\ge 10$ mm in diameter when measured with a caliper (e.g., skin nodules). Photographic documentation with a color photo and a ruler is recommended to determine dimensions. If a lesion is accessible to both clinical evaluation and imaging, imaging should be preferred as it is more objective and allows for subsequent audit.
Chest radiography: computed tomography (CT) is preferred over radiography, especially in cases where disease progression is an important endpoint. CT has greater sensitivity in detecting new lesions. However, lesions visualized on a chest X-ray can be considered measurable if they are clearly defined and surrounded by aerated lung.
CT and MRI: CT is currently considered the most preferred and reproducible method for measuring lesions selected for response evaluation. This guideline defines lesion measurability on CT based on the assumption that slice thickness is no greater than 5 mm. In cases where CT with a slice thickness of more than 5 mm is used, the minimum size of a measurable lesion must be twice the slice thickness. MRI is also acceptable in certain situations, especially for examining specific body regions.
Ultrasound (US): Ultrasound is not a reliable method for measuring tumor lesion sizes and should not be used as the primary evaluation method. Ultrasound examinations are not fully reproducible across repeat evaluations and are operator-dependent, making it difficult to obtain comparable data at different time points. If new lesions are detected on US during an examination, confirmation by CT or MRI is recommended. If there are contraindications to CT (e.g., radiation concerns), MRI may be considered as an alternative.
Endoscopy, laparoscopy: The use of these methods is not recommended for objective tumor evaluation. However, they may be useful in confirming a complete pathological response (e.g., via biopsy) or in establishing recurrence in studies where recurrence following complete resection or remission is an endpoint.
Tumor markers: Tumor markers cannot be used alone to determine objective tumor response. If marker levels were initially elevated, their normalization may indicate a complete response (CR). Since markers are disease-specific, their use must be clearly described in protocols depending on the tumor type. Separate guidelines exist for CA-125 (recurrent ovarian cancer) and PSA (recurrent prostate cancer). In addition, the Gynecologic Oncology Group has developed CA-125 progression criteria that are integrated with objective tumor assessment for use in first-line ovarian cancer trials.
Cytology and histology: These methods can be used to differentiate between partial and complete response in rare cases if provided by the protocol (e.g., in testicular tumors, where residual benign tissue may be present). If exudative manifestations appear or worsen (e.g., pleural effusion), cytological confirmation of malignancy can be used to distinguish between stable disease/response and disease progression, provided the response or stabilization criteria for measurable lesions have been met.
4. Assessment of overall tumor burden and measurable disease
4.1. For assessing objective response to treatment or subsequent progression
it is necessary to determine the baseline overall tumor burden (prior to treatment), the value of which is then used as a reference point for all subsequent measurements.
4.2. Documentation of target and non-target lesions at baseline
If multiple measurable lesions are identified at baseline, a maximum of five lesions in total should be selected, with no more than two lesions per organ, to represent all involved organs. These lesions are considered target lesions and must be recorded and measured on baseline imaging. (Example: if one or two organs are involved, a maximum of two or four lesions will be selected, respectively.) Target lesions should be selected based on:
their size (longest diameter),
representativeness of the affected organs,
and suitability for reproducible repeated measurements.
If the largest lesion does not allow for reproducible measurement, the next largest reproducible lesion should be selected.
Special attention to lymph nodes:
Lymph nodes are normal anatomical structures that may be visualized even in the absence of metastatic involvement. As stated in Section 3, pathologically altered lymph nodes to be assessed as target lesions must have a short axis ≥ 15 mm on CT. Only the short axis of the node is included in the sum of measurements calculation. The short axis is the smaller of two measurements recorded in the imaging plane (in CT, most commonly the axial plane; in MRI, axial, sagittal, or coronal). For example, a lymph node measuring 20 × 30 mm (in the axial plane) has a short axis of 20 mm and is considered a measurable malignant node. It is this value—20 mm—that must be recorded.
4.3. Response evaluation criteria
4.3.1. Evaluation of target lesions
Table G3-1. Target lesion evaluation
Category | Criteria |
|---|---|
Complete Response (CR) | Disappearance of all target lesions. All pathological lymph nodes (including non-target ones) must decrease to a short axis of less than 10 mm. |
Partial Response (PR) | At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Disease Progression (PD) | At least a 20% increase in the sum of diameters of target lesions compared to the smallest sum recorded since treatment started (including the baseline sum if that is the smallest), and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. |
Stable Disease (SD) | Neither sufficient shrinkage to qualify for CR nor sufficient increase to qualify for PR. |
4.3.2. Special notes on target lesion evaluation
Lymph nodes: even if lymph nodes regress to < 10 mm (normal), their actual short axis value should be recorded at each assessment, even when complete response is achieved. Therefore, the sum of measurements may not be zero even in the presence of CR.
Lesions that become "too small to measure": if a lesion is visualized but the radiologist cannot accurately measure its size, the following should be done:
assign 0 mm if, in the radiologist's opinion, the lesion has disappeared;
assign 5 mm if the lesion is "barely discernible" but present.
This avoids false conclusions regarding response or progression.
Fusion or fragmentation of lesions:
Upon fragmentation: the lengths of all visible parts are summed.
Upon fusion: the largest diameter of the combined lesion is measured.
4.3.3. Evaluation of non-target lesions
Table G3-2. Non-target lesion evaluation
Category | Criteria |
|---|---|
Complete Response (CR) | Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes — < 10 mm in short axis. |
Non-CR / Non-PD | Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. |
Progression (PD) | Unequivocal progression of existing non-target lesions. The appearance of new lesions is also considered progression. |
4.3.4. Notes on non-target lesion progression
If the patient also has measurable lesions, progression of non-target lesions is considered unequivocal only if there is significant overall clinical deterioration, even in the presence of PR or SD in target lesions.
If the patient has only non-target lesions, progression is considered unequivocal if the degree of deterioration is comparable to a 73% increase in tumor volume (equivalent to a 20% increase in diameter).
4.3.5. New lesions
The appearance of new malignant lesions indicates disease progression.
The lesion must be unequivocally new—it is important to exclude artifacts, methodological changes, or natural changes (e.g., necrosis in response to therapy).
If a lesion is detected in an area not covered by baseline imaging, it is considered new.
In case of equivocal findings, treatment may continue until the next assessment for confirmation.
Best overall response is the best response recorded from the start of the treatment until disease progression/recurrence, taking into account any requirement for confirmation where confirmatory measurements are clinically indicated.
Sometimes a response may be recorded after the cessation of therapy, so the protocol should clearly state whether such post-therapy assessments are considered when determining the best response.
If a patient starts a new therapy before progression, the protocol should also specify whether this affects the response classification.
Determination of the best response must take into account:
changes in target and non-target lesions,
appearance of new lesions,
need for response confirmation.
Table G3-3. Time-point response: patients with target (± non-target) lesions
Target lesions | Non-target lesions | New lesions | Overall response |
|---|---|---|---|
CR | CR | No | CR |
CR | Non-CR / Non-PD | No | PR |
CR | Not evaluated | No | PR |
PR | CR | No | PR |
PR | Not PD or not all lesions evaluated | No | PR |
ST | Not PD or not all lesions evaluated | No | ST |
Not all evaluated | Not PD | No | NE (Not Evaluable) |
CR | Any | Present or absent | CR |
Any | CR | Present or absent | CR |
Any | Any | Yes | CR |
Notations:
CR — Complete Response
PR — Partial Response
SD — Stable Disease
PD — Progressive Disease
NE — Not Evaluable
Appendix G4. Melanoma-specific Graded Prognostic Assessment (GPA) scale [515]
Russian title: Graded Prognostic Assessment (GPA).
Original title (if applicable): The Graded Prognostic Assessment (GPA).
Source (official website of the developers, validation publication):
Original publication: Sperduto PW, Jiang W, Brown PD, et al. Estimating Survival in Melanoma Patients with Brain Metastases: An Update of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA). Int J Radiat Onc Biol Phys 2017, on-line 10/17/17, print issue 11/15/17. [621,622].
Type: rating scale.
Purpose: estimation of survival prognosis in patients with melanoma brain metastases.
Content, key, and template are available at https://brainmetgpa.com
Prognostic parameters / Points | 0 points | 0.5 points | 1 point |
|---|---|---|---|
Karnofsky performance scale | < = 70 | 80 | 90-100 |
Age, years | > = 70 | < 70 | N/A |
Number of brain metastases | > = 5 | 2-4 | 1 |
Extracranial metastases | Present | N/A | Absent |
BRAF gene mutation | Absent or unknown | Present | N/A |
Total score | Median overall survival (months) according to GPA |
|---|---|
0-1 | 5 |
1,5 – 2,0 | 8 |
2,5 -3,0 | 16 |
3,5 – 4,0 | 34 |