Uveal Melanoma: Clinical Guidelines

List of Abbreviations

To assess the correspondence between terms used in the clinical practice guideline and terms from the current nomenclature of medical services, see Table A3-1 (Appendix A3)

ALT – alanine aminotransferase

AST – aspartate aminotransferase

BT – Brachytherapy for ocular neoplasms using a radioactive ophthalmic applicator

IV – intravenous

PFS – progression-free survival

IOP – intraocular pressure

WHO – World Health Organization

GGT – gamma-glutamyl transferase

Gy – Gray

CI – confidence interval

Malignant neoplasm – malignant neoplasm

CT – computed tomography

LDH – lactate dehydrogenase

PT – physical therapy

mAb – monoclonal antibodies (ATC code: L01XC)

ICD-10 – International Classification of Diseases 10th Revision

MRI – magnetic resonance imaging

CM – choroidal melanoma

OA – ophthalmic applicator

OS – overall survival

ODM – oculodermal melanosis

OCT – optical coherence tomography

HR – hazard ratio

PET – positron emission tomography

PET/CT – positron emission tomography combined with computed tomography

DLC – destructive laser coagulation

SFD – single focal dose

pT – pathomorphological classification

RFA – radiofrequency ablation

TFD – total focal dose

SRT – stereotactic radiotherapy

SRS – stereotactic radiosurgery

TACE – transarterial chemoembolization

FNAB – fine-needle aspiration biopsy

TTT – transpupillary thermotherapy

US – ultrasound examination

UM – uveal melanoma

FFA – fundus fluorescein angiography

CCDS – ciliochoroidal detachment

ALP – alkaline phosphatase

AJCC – American Joint Committee on Cancer

ASCO – American Society of Clinical Oncology

CTCAE – Common Terminology Criteria for Adverse Events

ECOG – Eastern Cooperative Oncology Group

RECIST – Response Evaluation Criteria in Solid Tumors

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

UICC – Union for International Cancer Control

** – vital and essential drugs

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

Terms and Definitions

CTLA4 – cytotoxic T-lymphocyte-associated protein 4, also known as CD152. Functions as a receptor with B7.1 or B7.2 molecules as ligands.

PD-1 – programmed cell death protein 1 receptor.

CTLA-4 inhibitor (also referred to in the text as CTLA-4 blocker, anti-CTLA-4 mAb, CTLA-4 antagonist, anti-CTLA-4) – ATC class L01FX (Other monoclonal antibodies) – a monoclonal antibody that blocks the inhibitory signals of the CTLA-4 cascade.

PD-1 inhibitor (also referred to in the text as anti-PD-1 mAb, anti-PD-1, anti-PD-1/PD-L1 mAb) – L01FF PD-1/PD-L1 (programmed cell death protein 1 / programmed cell death ligand 1) inhibitors – monoclonal antibodies that block the interaction between the programmed cell death receptor (PD-1) and its ligands.

Block excision – surgical treatment of a tumor in the iridociliochoroidal region involving the en bloc removal of the tumor along with adjacent tissues as an iridectomy, iridocyclosclerectomy, cyclochoroidsclerectomy, and iridocyclochoroidsclerectomy, encompassing 2 mm of surrounding healthy tissue.

Brachytherapy (BT) – Brachytherapy for ocular neoplasms – a method of contact irradiation of a tumor using radioactive ophthalmic applicators; it is the "gold standard" for eye-sparing treatment of intraocular tumors.

Computed tomography (CT) – an imaging method based on mathematical cross-sectional reconstruction of images obtained using X-ray radiation.

Magnetic resonance imaging (MRI) – a method of obtaining tomographic medical images for the examination of internal organs and tissues using the phenomenon of nuclear magnetic resonance.

Optical coherence tomography (OCT) – a non-invasive, informative, and sensitive method that allows quantitative and qualitative assessment of the retina, providing in vivo "optical biomicrometry" of the adjacent vitreous body and choroid.

Proton beam therapy – a type of external beam radiation therapy using proton energy. The proton beam has minimal lateral scatter, a defined range in biological tissues, and a peak of ionization at the end of its range (Bragg peak). This allows for conformal dose distributions matching the volume and shape of the tumor with a high dose gradient at the boundary between the tumor and healthy tissues, thereby delivering radical doses of radiation to the neoplasm while minimizing radiation damage to healthy ocular tissues.

Destructive laser coagulation (DLC) – a method of laser tumor destruction using a green laser with a wavelength of 532 nm.

Gamma Knife stereotactic radiosurgery – high-precision single-fraction irradiation with convergence of multiple beams at an isocenter with a steep dose gradient for small pathological lesions, strictly utilizing a stereotactic frame. The Gamma Knife allows for the delivery of a high tumoricidal dose to the tumor (approximately 30 Gy), but the volume of irradiated healthy tissue is significant compared to proton beam therapy.

Transpupillary thermotherapy (TTT) – thermotherapy of retinal and choroidal neoplasms – a laser treatment method involving thermal exposure to the tumor (42–60 °C) using an 810 nm diode laser, the mechanism of action of which is related to subcoagulative necrosis, thrombosis, and necrosis of the tumor's own blood vessels.

Fine-needle aspiration biopsy (FNAB) – a method of in vivo cytological diagnosis that provides a certain degree of diagnostic certainty regarding melanoma and is performed in the operating room.

Ultrasonography (US) of the eyeball and orbit – a non-invasive, contact, highly informative instrumental method in the diagnosis of UM and monitoring the efficacy of its local treatment.

Fundus fluorescein angiography (FFA) – an instrumental diagnostic method for fundus pathology using intravenous sodium fluorescein contrast agent (ATC S01JA Coloring agents).

Second phase of rehabilitation – inpatient rehabilitation in medical organizations (rehabilitation centers, rehabilitation departments) during the early recovery period of the disease, the late rehabilitation period, or the period of residual disease symptoms.

Radiological response assessment – assessment of treatment response using radiological imaging (computed tomography, magnetic resonance imaging, positron emission tomography, radiography, etc.) compared with prior radiological imaging in accordance with one or more response evaluation criteria (such as RECIST or WHO).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Uveal melanoma is a tumor of neuroectodermal origin developing from melanocytes of the uveal tract (choroid, ciliary body, iris) [1-4].

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

Uveal melanoma (UM) is a rare subtype of melanoma (accounting for 3.7–5% of all melanoma types) that arises from the malignant transformation of melanocytes in the vascular tunic of the eyeball. The risk of UM is increased in fair-skinned individuals, as well as in those with blue and grey irises [5–7]. In the United States, the vast majority of UM cases occur in the white population—97.8% [8–10]. The impact of ultraviolet radiation on the development of ocular melanoma remains incompletely understood. Some authors consider the data suggesting an effect of natural ultraviolet radiation on UM development to be unconvincing [6, 11]. At the same time, a role for artificial ultraviolet radiation (tanning beds) in the development of uveal melanoma is noted [12, 13]. The literature discusses whether UM develops against the background of dysplastic nevus syndrome, ocular and oculodermal melanosis, or arises de novo. For instance, according to E. Richtig et al., one-third of UM patients (35.3%) had more than five dysplastic nevi, compared to 1.2% in the general population [14]. The relative risk of developing choroidal melanoma in patients with dysplastic nevi is comparable to that of cutaneous melanoma: the relative risk (RR) ratios were 4.36 and 4.32, respectively [5, 15]. An association between oculodermal melanosis and UM among the white population is also observed. According to A.D. Singh, the lifetime risk of developing UM is estimated at 2.6 × 10−3. The biological basis for the development of UM in ocular and oculodermal melanosis is the high number of melanocytes in the uveal tract in this category of patients [16–24]. One of the mechanisms of UM development is genetic predisposition. Most commonly, hereditary UM is one of the manifestations of the so-called TPS syndrome, caused by germline mutations in the BAP1 gene (OMIM ID #614327 – accounting for about 3% of all UMs); isolated cases of UM have also been described with germline mutations in the MBD4 gene (OMIM ID *603574) and in Lynch syndrome (OMIM ID #276300).

1.3 Epidemiology of the Disease or Condition

Among malignant eye tumors, melanoma is the most common. About 95% of all ocular melanomas originate in the vascular (uveal) tract of the eye (anterior—iris, and posterior—ciliary body and choroid), with the remaining 5% divided among melanomas of the conjunctiva, orbit, and eyelid [9, 10].

The annual global incidence of UM is 6 cases per 1 million population [9, 10]. The average European incidence rate for UM ranges from 5 to 8 per 1 million residents [1, 25, 26]. The variation in incidence rates is related to geographic latitude: over 8 cases per 1 million are registered in Northern Europe (Norway and Denmark), compared to 2 cases per 1 million in Southern Europe (Spain and Italy). Data indicating that UM is less common in residents of southern countries than in those of northern regions are confirmed by other studies [27, 28]. This epidemiological feature may be related to the protective property of pigmentation [26]. In European countries, UM ranks among the most frequent rare-site melanomas (47.8%) [1].

In the Russian Federation, UM is recorded together with other malignant neoplasms of the eye and its adnexa; however, among other types of eye malignancies, UM accounts for up to 70% of all newly diagnosed cases.

In 2023, 1,184 individuals were diagnosed with malignant neoplasms of the eye and its adnexa in the Russian Federation [29]. In 2023, the crude incidence rate was 0.74 per 100,000 population for men and 0.87 per 100,000 population for women (both sexes combined – 0.81 per 100,000).

The age-standardized incidence rate was 0.58 and 0.56 per 100,000 population for men and women, respectively. In the structure of malignant neoplasms of the eye and its adnexa, it accounts for 0.18%.

The average annual growth rate of the crude incidence rate over 10 years is +1.77% (both sexes combined) [29].

Mortality rates from malignant neoplasms of the eye and its adnexa are not published separately in Russia [29].

At the end of 2023, there were 13,810 patients under active follow-up (9.44 per 100,000 population), of whom 9,253 patients (67%) had been followed for 5 years or more. The caseload accumulation index was 12.87, and the mortality rate was 2.76% (compared to 2.55% in 2022) [30].

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 topographic location of the primary site [31]:

• C69.3 Malignant neoplasm of choroid;

• C69.4 Malignant neoplasm of ciliary body;

• C69.8 Malignant neoplasm of overlapping lesion of eye and adnexa.

These clinical guidelines focus on malignant neoplasms of the choroid (C69.3), ciliary body (C69.4), and overlapping lesions of the eye and adnexa (C69.8), because the therapeutic approaches for these forms differ from those for, e.g., C69.0, which are covered in the clinical guidelines for cutaneous and mucosal melanoma.

1.5 Classification of the disease or condition

1.5.1. International Histological Classification of Melanocytic Tumors

WHO Classification, 4th Edition, 2018 [32, 33]:

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

1.5.2. Staging

Staging of cutaneous melanoma according to the AJCC/UICC TNM Classification, 8th Edition (2017) [34, 35].

The classification is based on pretreatment data obtained from examination and various ocular imaging techniques (ultrasonography and orbital CT/MRI) to assess the T category, supplemented by findings from surgical intervention or examination of the surgical specimen. The classification below applies exclusively to tumors of the iris, ciliary body, and choroid.

The T category reflects the extent of the primary tumor. T-category classification is possible only after removal of the primary tumor and its histological examination (Table 1).

Table 1. T Category (Primary Tumor)

¹ _{Iris melanoma originates from and is predominantly located in this region of the vascular tunic of the eye. If less than half of the tumor volume is located in the iris, the tumor may have originated in the ciliary body and should be classified accordingly.}

Table 2 also shows the relationship between the T category and the thickness and basal diameter of the primary uveal melanoma.

Table 2. Classification of uveal and ciliary body melanoma according to thickness and diameter (T category) [36].

Comment:

1) In clinical practice, the largest basal tumor diameter can be estimated in optic disc diameters (disc diameters [DD], on average: 1 DD = 1.5 mm). Tumor thickness can be estimated in diopters (on average 2.5 D = 1 mm). However, more precise measurements are provided by methods such as ultrasonography and fundus photography. Ciliary body involvement can be evaluated using a slit lamp (biomicroscopy), ophthalmoscopy, gonioscopy, and transillumination (diaphanoscopy). Nevertheless, high-frequency ultrasonography (ultrasound biomicroscopy) is used for a more accurate assessment (see Table A3-1). Scleral extension is assessed visually before and during surgery, as well as by ultrasound, computed tomography, or magnetic resonance imaging [36].

2) When pathomorphological examination is performed after tissue fixation, the diameter and thickness of the tumor may be underestimated due to tissue shrinkage [36].

N category indicates the presence or absence of regional lymph node metastases (Table 3).

Regional lymph nodes are considered to be:

• Preauricular lymph nodes

• Submandibular lymph nodes

• Cervical lymph nodes

Table 3. N category (regional lymph node involvement) [36]

M category characterizes the presence or absence of distant metastases (Table 4).

Table 4. M category (distant metastases) [36]

Stage grouping is presented in Table 5.

Table 5. Stage grouping [36]

Pathomorphological classification pT

Criteria for assigning the pT category correspond to those for the T category.

Histological type (G) [36]

GX – type cannot be assessed;

G1 – spindle-cell melanoma (≥ 90% spindle cells, ≤ 10% epithelioid cells);

G2 – mixed-cell melanoma (proportion of spindle and epithelioid cells > 10%, but < 90%);

G3 – epithelioid-cell melanoma (≤ 10% spindle cells, ≥ 90% epithelioid cells).

1.6 Clinical presentation of the disease or condition

Iris melanoma. Nodular form appears as an ill-defined nodule. Color ranges from pink to dark brown. Vessels are visible on the tumor surface, contours are indistinct. Mixed form is characterized by the presence of a nodule against a background of planar growth with pigment dispersion around it and tumor satellites on the iris surface. The surface of the nodule is uneven, the depth of the anterior chamber is uneven. Tumor invasion into the pupillary dilator leads to a change in its shape. Extension of the neoplasm into the posterior chamber leads to dislocation and opacity of the lens. Tumor satellites can be seen on the iris surface. Invasion of the anterior chamber angle by the tumor, depending on the extent of invasion, leads to persistent ocular hypertension. Diffuse form of melanoma is characterized by planar growth with pigment dispersion around it and invades the anterior chamber angle of the eye, early leading to persistent hypertension. Annular form, as a variant of the diffuse form, grows slowly and asymptomatically and manifests as iris heterochromia and smoothing of its pattern. The surface acquires a shagreen appearance. This form leads to an increase in intraocular pressure. Tapioca melanoma is a rare form. It grows slowly and asymptomatically. Pale gray translucent nodules with a tendency to coalesce are visible on the iris surface. Tumor vessels are visible. Hyphema may occur. Pigment accumulation is present at the pupillary margin. Iris melanoma, spreading along the uveal tract, forms an iridociliary melanoma. Similarly, ciliary body melanoma can spread to the iris, forming an iridociliary tumor form. Further progression of these tumors results in an iridocyclochoroidal melanoma.

Ciliary body melanoma. Isolated involvement of the ciliary body is rare; combined involvement—iridociliary or ciliochoroidal—is much more common. The tumor can be pigmented or amelanotic, grows slowly and asymptomatically for a long time, and hypotony may appear in the early stages of neoplasm growth. An increase in the size of the neoplasm leads to lens dislocation and local opacity of its capsule, causing visual impairment. Invasion into the anterior chamber angle leads to the appearance of iris folds and false iridodialysis. Tumor invasion into the iris causes a change in the pupil shape, its margin flattens, and the light reflex is reduced or absent. Congestive tortuous episcleral vessels appear in the tumor growth sector. Neovascularization of the iris and an increase in IOP are possible.

Choroidal melanoma. The majority of choroidal melanomas (CM) (80–90%) are located postequatorially, and about ¼ are in the region of the equator of the eye. Binocular and multicentric tumor forms are very rare (0.1–0.3%). CM has a nodular growth pattern or, less commonly, a diffuse pattern. In the initial stage of growth, choroidal melanoma appears as a rounded, slightly prominent gray-green or yellow-brown lesion with indistinct, uneven borders. Areas of orange pigment (lipofuscin) are often visible on the tumor surface. As the melanoma grows, its own vessels appear, and pigmentation may increase. Tumor growth is accompanied by retinal detachment resulting from transudation and exudation from the neoplasm and retinal vessels. When the Bruch's membrane is breached, a "mushroom-shaped" tumor may form. Single or multiple hemorrhages frequently appear on the melanoma surface. As a rule, retinal hemorrhages surrounding the tumor are observed with rapidly growing neoplasms. The growth of CM may be accompanied by indirect signs: retinal detachment, uveitis, iridocyclitis, scleritis, iris rubeosis, dilation of episcleral vessels, hemophthalmos, secondary hypertension, endophthalmitis, lens opacity, and ocular subatrophy. Diffuse CM is characterized by widespread thickening of the choroid; its thickness usually does not exceed 2.5 mm, but it has a large base diameter. Diffuse CM is characterized by early tumor invasion into the optic nerve and spread beyond the sclera [25, 37-40].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

1. complaint and anamnesis data;

2. physical examination data;

3. instrumental examination data;

4. in some cases, pathomorphological examination data of surgical or biopsy material, or cytological examination of the tumor aspirate.

2.1 Complaints and Anamnesis

Introduction to the subsection. Main complaints:

• visual impairment;

• distortion of objects;

• appearance of a "curtain" before the eye;

• appearance of dilated tortuous vessels on the surface of the eye;

• change in iris color and appearance of spots.

Comment: upon the appearance of the above complaints, the physician (general practitioner, therapist, neurologist, etc.) refers the patient to an ophthalmologist.

2.2 Physical Examination

2.3 Laboratory Diagnostics

– size of the primary tumor (basal diameter and thickness) (except for cases of partial removal – tumor biopsy);

– tumor localization;

– involvement of ocular membranes (their infiltration, invasion, detachment);

– status of resection margins (in block excisions);

– presence of extraocular extension and its dimensions;

– length of the optic nerve, its infiltration by the tumor at the resection margin (after enucleation, exenteration);

– in the tumor tissue: mitotic count per high-power field, tumor pigmentation, lymphocytic and macrophage infiltration, presence of necrosis, hemorrhages;

– histological type.

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

2.4 Instrumental Diagnostics

Comments: tier 1–3 ophthalmologists perform the aforementioned ophthalmological diagnostic methods and, upon detecting an intraocular tumor, refer the patient to a tier 3 medical institution for additional instrumental ophthalmological evaluation. Ophthalmoscopy is performed under maximum mydriasis (in the absence of patient contraindications to pupil dilation or synechiae).

Comments: ultrasound examinations are performed in a tier 3 medical institution. Ultrasound is the primary instrumental diagnostic method for intraocular tumors. Grayscale echography (B-mode) allows determining the size of the neoplasm (prominence and base diameter), the localization and extent of the tumor, and the state of the ocular membranes. Using color Doppler mapping and spectral Doppler flow analysis modes, the tumor's own neovascular network is detected, and hemodynamic characteristics of blood flow in the tumor vessels are recorded [69].

Comments: OCT is a highly informative non-invasive method that allows determining morphometric signs characteristic of choroidal melanoma (arcuate change in the choroidal profile, retinal thickening due to the accumulation of intra- and subretinal fluid, presence of diffuse or cystoid edema, neuroepithelial detachment, pigment disorganization in the retinal pigment epithelium with the formation of pigment foci and window defects, compression of choriocapillaries with a "shadow" effect, and neuroepithelial detachment in the area adjacent to the tumor) [71-74].

Comment: orbital CT and MRI are performed with a minimum slice thickness (0.5–1.0) mm in two mutually perpendicular projections.

2.5 Other Procedures

Comments:

1) In uveal melanoma, the "drivers" of carcinogenesis are somatic mutations in the "hotspots" of the GNAQ, GNA11 genes, and less frequently in other genes of the same signaling cascade (CYSLTR2, PLCB4, and possibly also PLCB3). Testing uveal melanoma tissue samples for mutations in GNAQ, GNA11, CYSLTR2, PLCB4, and PLCB3 genes is of substantial value for the differential diagnosis of uveal melanoma, but not for determining its prognosis [101-105].

2) "Modifier" molecular alterations appearing at later stages of carcinogenesis, such as 3p deletion, 8q amplification, and mutations in EIF1AX, SF3B1, SRSF2, and BAP1 genes, significantly correlate with individual metastatic risk in uveal melanoma [102-104]. Testing uveal melanoma tissue samples for 3p deletion, 8q amplification, and mutations in EIF1AX, SF3B1, SRSF2, and BAP1 genes is of substantial value for determining prognosis (for details, see Table 6).

3) "Driver" mutations in BRAF, NRAS, and KIT gene hotspots, characteristic of cutaneous and mucosal melanoma, are virtually absent in uveal melanoma (not a single reliably documented case exists). Testing uveal melanoma tissue samples for BRAF, NRAS, and KIT mutations is deemed impractical [101-105].

4) A small percentage of uveal melanoma cases (no more than 3%) is associated with a hereditary predisposition. Most frequently, the hereditary (familial) form of uveal melanoma is one of the manifestations of the so-called TPS syndrome, caused by germline mutations in the BAP1 gene (OMIM ID #614327 – approximately 2% of all uveal melanomas); isolated cases of uveal melanoma have also been reported with germline mutations in the MBD4 gene (OMIM ID *603574) and in Lynch syndrome (OMIM ID #276300). Testing uveal melanoma patients for germline mutations is advisable only when a hereditary nature of the disease is suspected (patient age under 45 years and/or bilateral uveal melanoma and/or multiple primary malignancies and/or a burdened family history). According to some data, the frequency of certain molecular alterations in uveal melanoma cells is: monosomy 3 – 52.2% (complete – 37.3%, partial – 14.9%), loss of heterozygosity in chromosome 1p – 29.1%, in chromosome 8p – 20.0%; RASSF1A gene methylation – 23.9%, GNAQ/GNA11 mutations – 90.0%. It has been proven that monosomy 3 significantly reduces the survival of uveal melanoma patients (down to 46.8%) [101-104].

Comments: main prognostic factors in uveal melanoma:

1) clinical – primary tumor size (T4 vs T1–T3), ciliary body involvement (present vs absent), extraocular extension (present vs absent);

2) morphological – tumor cell type (epithelioid vs mixed-cell vs spindle-cell);

3) molecular genetic – profile of molecular alterations in the tumor (see Table 7 and [104]).

Notes:

1. In case of discrepancy between prognostic information obtained by different methods, it is advisable to rely on the "worst" of the obtained options.

2. Consequently, molecular genetic testing for prognostic determination is indicated primarily for patients without clinical and morphological factors of unfavorable prognosis (i.e., patients with spindle-cell and mixed-cell T1–T3 melanoma without ciliary body involvement and without extraocular extension). However, this testing can also be used in patients with one or more unfavorable prognostic factors—in particular, to refine the prognosis ("poor" vs "very poor") and to address patient participation in adjuvant therapy clinical trials.

3. Evaluation of clinical, morphological, and molecular genetic prognostic factors in patients with metastatic uveal melanoma can be used to refine the strategy and tactics of antitumor treatment.

4. Testing for molecular genetic prognostic factors in uveal melanoma is recommended using two methods: cytogenetic and mutation testing. The routine use of a third method—expression profiling—cannot currently be recommended due to the lack of validated techniques available in Russia. Due to a significant percentage of prognostic discrepancy between methods [104], it is advisable to perform tests using both methods for each sample studied. In case of discrepancies in prognostic information obtained by different methods, it is recommended to rely on the "worst" of the obtained outcomes. Only validated testing techniques are permitted.

5. Testing for morphological and molecular genetic prognostic factors in uveal melanoma can be performed on both histological and cytological material. When using cytological material, it is not possible to distinguish between the three tumor types (epithelioid cell vs. mixed cell vs. spindle cell), and the morphological report must indicate the presence or absence of a significant number of epithelioid cells in the specimen. For molecular genetic testing of cytological material, only techniques specifically validated for this type of biological material should be used, paying special attention to input quality and quantity control of the provided material.

Table 6. Main molecular classes of uveal melanoma and their prognostic significance [104].

Notes.

* 8q↑ – increased copy number of the long arm of chromosome 8 (8q), 8p↓ – decreased copy number of the short arm of chromosome 8 (8p).

** Expression types 1 and 2 are multicomponent markers: the classification of a UM sample into one of them is determined using a special algorithm based on mRNA expression levels of several genes in tumor cells.

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

3.1 Treatment of Patients with Localized Forms of UM

Comments: local ablative treatment of UM (enucleation, orbital exenteration) is also performed in general-profile level 2–3 ophthalmology departments not specializing in ocular oncology. Orbital exenteration is also performed in oncological medical organizations (head and neck tumor departments).

Comments: local treatment of UM represents a set of ablative (enucleation, orbital exenteration) and organ-sparing procedures, including surgical (block excision), radiation, and laser methods, and is planned depending on the size and location of the primary tumor. Before planning local treatment, the patient is prescribed a complete clinical examination to rule out distant tumor metastases. In the presence of distant metastases, local treatment (enucleation) is performed for complications caused by tumor growth (pain syndrome, eye perforation, etc.). In the presence of a single distant metastasis, organ-sparing treatment is possible in exceptional cases.

3.1.1 Conservative treatment

Not performed.

3.1.2 Surgical treatment

Comment: organ-sparing treatment of UM is performed only in ophthalmology departments specializing in the treatment of ocular oncological diseases.

3.1.2.1 Surgical Treatment of Iridociliary Melanoma

Comments: local tumor removal – block excision consists of resecting the tumor en bloc with a margin of surrounding healthy tissues. The extent of the neoplasm determines the scope of surgery (iridectomy, iridocyclitis/iridocycloectomy, iridocycloscleroretinectomy, and choroidsclerectomy). To restore the diaphragmatic function of the iris, reduce light aberrations, and improve visual acuity after iris tumor removal, iridoplasty is performed simultaneously, which is possible if the resulting iris defect does not exceed 5 hours of its circumference. The removed tissue block is subject to mandatory pathological examination. Performed only in ophthalmology departments specializing in the treatment of ocular oncological diseases.

Absolute contraindications to block excision:

ᴑ secondary hypertension;

ᴑ absence of vision;

ᴑ iris neovascularization;

ᴑ annular growth of the neoplasm along the structures of the iridocorneal angle;

ᴑ extrabulbar tumor growth;

ᴑ severe concomitant somatic and mental pathology.

3.1.2.2 Surgical Treatment of Ciliary Body and Choroidal Melanoma

Comments: performing eyeball enucleation for UM requires compliance with certain rules: the surgery is performed under general anesthesia using microsurgical techniques; all manipulations with the eye and extraocular muscles are performed gently, avoiding deformation and pressure on the eye. Eyeball enucleation must be performed with simultaneous formation of a locomotor stump using an orbital implant*** in the absence of extrabulbar growth. The length of the optic nerve after neurectomy during eyeball enucleation is at least 10 mm. At the end of the surgery, an orbital implant*** is implanted into the conjunctival cavity, and the enucleated eye is sent for pathological examination.

Comments: orbital exenteration is performed under general anesthesia, with simultaneous plasty of the orbital cavity, using microsurgical techniques. Ectoprosthetic rehabilitation of patients is carried out in a delayed manner after the surgical wound has healed.

3.1.3 Radiation Therapy

Contact radiation therapy is performed in ophthalmological inpatient facilities specializing in providing care to patients with ocular oncological diseases.

External beam radiation therapy is performed in radiation departments by radiation oncologists.

Comments: BT using Ru106 + Rh106 isotope applicators is used for tumor prominence up to 6–7 mm; Sr90 + Y90 isotope applicators are used for tumor thickness not exceeding 3.0 mm. The size of the applicator is chosen based on the tumor diameter and must exceed it by 2 mm; the optimal radiation dose for BT is calculated individually taking into account the size, location, and clinical presentation of the tumor, required to irradiate its entire volume, and is 120–140 Gy to the apex of the tumor when using Ru106 + Rh106 applicators and 160–180 Gy when using Sr90 + Y90 isotopes. BT is primarily performed for UM and melanomas of the ciliochoroidal localization, but in some cases can also be performed for iridociliary tumor localization.

Contraindications to BT:

1. Exceeding the specified tumor dimensions;

2. Suspected tumor extension beyond the sclera;

3. Ocular hypertension.

Relative contraindications to BT:

ᴑ severe and moderate blood disorders (leukopenia, agranulocytosis, poikilocytosis, anemia of various origins, hemophilia, etc.);

ᴑ acute inflammatory diseases of the eye and its adnexa;

ᴑ hemophthalmos;

ᴑ extensive retinal detachment;

ᴑ severe concomitant somatic and mental pathology.

BT should be performed under general anesthesia. When high doses are used (over 1100–1300 Gy to the sclera) simultaneously with brachytherapy, after removing the applicator, scleral reinforcement with donor sclera is performed [41, 137, 140]. A repeat course of treatment is possible if residual tumor persists after BT. The choice of the repeat treatment method depends on the tumor parameters and clinical presentation.

Comments: proton beam therapy is an external beam radiation therapy method for uveal melanoma. Post-radiation resorption after proton beam therapy is a prolonged process. The most common complication of proton beam therapy is radiation cataract; glaucoma, retinopathy, retinal detachment, and scleral necrosis occur less frequently.

Comment: laser treatment of uveal melanoma is an effective method of local tumor destruction that preserves visual function (except for centrally located tumors) and leads to minimal side effects compared to radiation therapy. Laser treatment can be performed on an outpatient basis, does not require anesthesia, and is suitable for somatically compromised patients. Laser tumor destruction is performed provided that the optical media of the eye are clear, with maximum drug-induced mydriasis. Laser treatment of uveal melanoma includes destructive laser photocoagulation (DLP), which is used for tumor thickness of no more than 1.5 mm and a maximum base diameter of up to 10 mm using a 532 nm diode green laser, and transpupillary thermotherapy (TTT (see Table A3-1), which is used for tumor thickness of no more than 2.5 mm, tumor base diameter of no more than 10 mm using an 810 nm diode laser. Laser treatment can be used either as a standalone treatment method or as an adjunct to other treatment modalities. Laser treatment can be performed for primary uveal melanoma as well as for residual uveal melanoma and continued growth.

3.1.4 Supportive Care in Local Treatment of Uveal Melanoma

• Depending on the patient's condition, presence of complications, and the course of the postoperative or post-radiation period, it is recommended to prescribe supportive drug therapy after local surgical and radiation treatment (medicines are prescribed in strict accordance with their official instructions for use) [25, 37, 39, 40]:

  • Instillations (anti-inflammatory drugs, anti-infective drugs or antibiotics, antiglaucoma drugs and miotics, other drugs for the treatment of eye diseases (including those with a keratoprotective effect), mydriatic and cycloplegic drugs).

  • Systemic (analgesics, non-steroidal anti-inflammatory and antirheumatic drugs, systemic antihistamines, systemic corticosteroids).

  • Local (glucocorticoids as short- and long-acting parabulbar injections).

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

3.2 Adjuvant Therapy After Radical Treatment of Primary Uveal Melanoma

Comment: adjuvant therapy for uveal melanoma requires further scientific study. Whenever possible, patient participation in clinical trials of adjuvant therapy is preferred.

3.3 Treatment of Advanced / Metastatic Forms of Uveal Melanoma

3.3.1 Local treatment

Introduction to the subsection: uveal melanoma most frequently metastasizes to the liver (according to studies, in 70–90% of all cases), lungs (29%), bones (17%), skin (12%), and lymph nodes (11%). In 46% of patients, the liver is the only organ affected by metastases, and in only 11% of patients with metastatic disease is the liver unaffected [46, 47, 147, 148]. The main features of metastasis are the absence of lymphatic vessels in the eye and the tropism of uveal melanoma cells to the liver parenchyma. In some cases, the features of uveal melanoma metastasis determine the treatment options (surgical treatment or local treatment of metastatic liver disease). Surgical treatment is infrequently used, given the often extensive prevalence of the metastatic process and, consequently, the impossibility of radical surgery. Recently, the results of clinical studies on the surgical treatment of metastatic uveal melanoma conducted in selected cancer institutes have been published. In a study conducted at the Curie Institute (France) out of 798 patients with uveal melanoma liver metastases, 250 patients underwent surgery. In 76 patients (29% of those operated on), visually radical removal of metastases (R0) was achieved, which accounted for 9% of the total patient population with metastases. The median survival in the radically operated group (R0) was 27 months vs. 11 months in the non-radically operated group. When analyzing these data, it should also be taken into account that surgical treatment was performed in patients with a favorable prognosis (based on the biological properties of the primary tumor), and the scope of surgery was radical (R0). In another single-center study, out of 73 patients with uveal melanoma liver metastases, 35 patients underwent cytoreductive surgeries. In the operated patients, the median overall survival was 23 months, and in the non-operated group, 6.8 months. Thus, retrospective studies show that surgical resection of solitary metastatic lesions in the liver can be curative with careful patient selection.

Comments: the meta-analysis included 22 studies involving 579 patients who underwent liver resection. The progression-free survival (PFS) median ranged from 8 to 23 months, and the overall survival (OS) median from 14 to 41 months, with a follow-up period of 9 to 59 months. Meanwhile, for the group of patients who successfully underwent R0 resection, it was 22–66 months, and for R2 resection, 10–16 months, while a reduction in the risk of death was observed by 48% when performing R0 compared to R1/R2 (95% CI, 0.37–0.73). There was also a 68% reduction in the risk of death among patients undergoing resection compared to patients whose treatment did not include surgery (HR 0.32, 95% CI 0.22–0.46) [155].

• For patients with isolated unresectable metastatic liver disease who have a satisfactory general condition, preserved liver function, and a total metastatic liver involvement volume of no more than 50 %, isolated hepatic pervaporation (IHP) performed by an oncologist is recommended. The use of IHP leads to improved survival rates in these patients [157-159].

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

Comments: It is advisable to perform IHP in a highly specialized inpatient facility equipped with a cardiopulmonary bypass machine. #Melphalan** at a dosage of 1.5 mg/kg is used as the antitumor agent. Before administering #melphalan** into the liver, it is necessary to ensure there is no leakage into the systemic circulation. The optimal duration of IHP is 60 minutes. According to a meta-analysis by M.S. Bethlehem et al. (2021), the median overall survival in the patient group treated with IHP was 17.1 months [159]. In the randomized multicenter clinical trial SCANDIUM, the median progression-free survival was 7.4 months in the IHP group versus 3.3 months in the control group (95 % CI from 0.12 to 0.36), while the median hepatic progression-free survival was 9.1 months in the IHP group versus 3.3 months in the comparison group (95 % CI from 5.6 to 13.4). The median overall survival was 21.4 months versus 17.3 months (p=0.11) [158].

Comment: Liver TACE is performed with minimal impact on the intact parenchyma. For nodular lesions, selective (superselective) transarterial chemoembolization is performed using microspheres (150–600 µm in diameter) in a solution with a chemotherapy drug, or TACE with drug-eluting microspheres (with an antitumor drug adsorbed on their surface (ATC code L01)). For multifocal lesions, oily chemoembolization (oily emulsion + antitumor drug) is performed. In the case of bilobar involvement, staged lobar TACE is performed. The first stage involves selective TACE of one liver lobe, and 4–6 weeks later, the second stage involves selective TACE of the other liver lobe. #Doxorubicin** at a dosage of 100 mg (per embolization), or #gemcitabine** 1–2 g (per embolization), or #carboplatin** 450 mg (per embolization) is used as the antitumor agent.

The number of TACE procedures can be multiple. In isolated metastatic liver disease, TACE can be performed as a first-line treatment or when systemic treatment is ineffective. A local response in the form of a reduction in tumor nodes in the liver or stabilization was observed after liver TACE in approximately 65-70 % of cases. Overall survival in this group of patients, calculated using the Kaplan–Meier method, was: 1-year 51.0 ± 9.5 %; 2-year 34.0 ± 15.2 %. The median survival was 12.9 months.

3.3.2 Systemic Therapy for Metastatic or Unresectable UM

Introduction to the subsection. Various medical treatment regimens are used to treat metastatic/advanced uveal melanoma (Table 7). The response rate ranges from 0 % to 20 %, with a median survival of 4 to 28 months [165, 166].

Comments: drug administration regimens are presented in Table 7.

Table 7. Medical therapy regimens for metastatic or unresectable uveal melanoma.

Comments: the prognosis for patients with metastatic uveal melanoma remains unfavorable, with a median OS of approximately 12 months after the detection of the metastatic process. Taking into account advances in the treatment of cutaneous melanoma and despite the different biology of uveal melanoma and cutaneous melanoma, most experts recommend that patients with metastatic uveal melanoma receive combination immunotherapy with PD-1 and CTLA-4 blocking monoclonal antibodies or PD-1 blocking monoclonal antibodies (PD-1/PD-L1 inhibitors (programmed cell death protein 1 / programmed cell death 1 ligand 1) as first-line therapy (in the absence of an opportunity to participate in a clinical trial) [168-174]. A meta-analysis by Yamada K. et al. demonstrated the superiority of the combination of PD-1 and CTLA-4 blocking monoclonal antibodies (PD-1/PD-L1 inhibitors (programmed cell death protein 1 / programmed cell death 1 ligand 1) compared to PD-1 blocking monoclonal antibody monotherapy – the objective response rate was 3.4 % (95 % CI 1.8–5.1) versus 12.4 % (95 % CI 8.0–16.9) (P < 0.001). The median overall survival was significantly higher in the group receiving the combination of PD-1 and CTLA-4 blocking monoclonal antibodies (PD-1/PD-L1 inhibitors (programmed cell death protein 1 / programmed cell death 1 ligand 1) than in the PD-1 blocking monoclonal antibody group – 16.3 months (95 % CI 13.5–19.7) versus 9.8 months (95 % CI 8.0–12.2) (P < 0.001). These data highlight the potential benefit of combination immunotherapy despite the higher risk of adverse events [165, 168, 201].

• If grade 3 immune-related adverse events develop during combination immunotherapy, after their resolution, switching to anti-PD-1 monotherapy (PD-1/PD-L1 inhibitors (programmed cell death protein 1 / programmed cell death 1 ligand 1) is recommended. Continuing combination immunotherapy up to 4 cycles is not recommended [204].

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

Comment: resuming combination immunotherapy or anti-PD-1 monotherapy (PD-1/PD-L1 inhibitors (programmed cell death protein 1 / programmed cell death 1 ligand 1) is possible as treatment re-induction if a response was achieved with its previous use and subsequent disease progression developed [204].

• All patients with melanoma receiving treatment with PD-1 or CTLA-4 monoclonal antibody blockers are recommended to undergo their initial radiological response assessment no earlier than 12 weeks from the start of therapy (in the absence of clinical deterioration). Follow-up imaging is performed every 8–12 weeks (in the absence of clinical deterioration) [205].

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

Table 8. Comparison of traditional criteria (using RECIST as an example) and response criteria for PD-1 or CTLA-4 monoclonal antibody blockers (PD-1/PD-L1 inhibitors (programmed cell death protein 1 / ligand 1) (mRECIST or irRC)).

• During chemotherapy, treatment efficacy is recommended to be assessed every 7–9 weeks, and during immunotherapy, every 11–13 weeks. To evaluate therapy efficacy, it is recommended to assess the patient's general condition and use the diagnostic imaging methods employed prior to therapy, as well as standard response criteria — RECIST 1.1 for chemotherapy, iRECIST or iRC for immunotherapy [206-208].

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

3.5 Anesthesia

The principles of pain management and optimal selection of analgesic therapy in patients with uveal melanoma suffering from chronic pain syndrome correspond to the pain management principles outlined in the clinical guidelines "Chronic Pain Syndrome in Adult Patients Requiring Palliative Medical Care" [209].

3.6 Supportive Care in Patients with Ocular Melanoma

3.6.1. Principles of prevention of acute and delayed nausea and vomiting during medical treatment of cutaneous melanoma

are outlined in the guidelines "PRACTICAL GUIDELINES FOR THE PREVENTION AND TREATMENT OF NAUSEA AND VOMITING IN CANCER PATIENTS" [210].

3.6.2. Principles of Treatment and Prevention of Bone Complications in Patients with Cutaneous Melanoma

are outlined in the guidelines "USE OF BONE-MODIFYING AGENTS (BMAs) FOR THE PREVENTION AND TREATMENT OF BONE PATHOLOGY IN MALIGNANT NEOPLASMS" [211].

3.6.3. Principles of Prevention and Management of Immune-Mediated Adverse Events

correspond to the principles outlined in the guidelines "PRACTICAL GUIDELINES FOR THE MANAGEMENT OF IMMUNE-MEDIATED ADVERSE EVENTS" [204].

3.6.4. Principles for the prevention and treatment of infectious complications and febrile neutropenia

correspond to the principles outlined in the guidelines "PRACTICAL GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF FEBRILE NEUTROPENIA" [212].

3.6.5. Principles for the prevention and treatment of hepatotoxicity

correspond to the principles outlined in the guidelines "CLINICAL GUIDELINES FOR THE CORRECTION OF ANTITUMOR THERAPY-INDUCED HEPATOTOXICITY" [213].

3.6.6. Principles for the prevention and treatment of cardiovascular complications

correspond to the principles outlined in the guidelines "PRACTICAL GUIDELINES FOR THE CORRECTION OF CARDIOVASCULAR TOXICITY OF ANTITUMOR DRUG THERAPY" [214].

3.6.7. Principles for the prevention and treatment of dermatological complications

correspond to the principles outlined in the guidelines "PRACTICAL GUIDELINES FOR THE MEDICAL TREATMENT OF DERMATOLOGICAL REACTIONS IN PATIENTS RECEIVING ANTITUMOR DRUG THERAPY" [215].

3.6.8. Principles of nutritional support

correspond to the principles outlined in the guidelines "PRACTICAL GUIDELINES FOR NUTRITIONAL SUPPORT IN CANCER PATIENTS" [216].

3.6.9. Principles for the prevention and treatment of thromboembolic complications

correspond to the principles outlined in the guidelines "PRACTICAL GUIDELINES FOR THE PREVENTION AND TREATMENT OF THROMBOEMBOLIC COMPLICATIONS IN CANCER PATIENTS" [217].

3.6.10. Principles for the prevention and treatment of nephrotoxicity

correspond to the principles outlined in the guidelines "PRACTICAL GUIDELINES FOR THE CORRECTION OF NEPHROTOXICITY OF ANTITUMOR DRUGS" [218].

3.6.11. Principles for the prevention and treatment of drug extravasation sequelae

correspond to the principles outlined in the guidelines "RECOMMENDATIONS FOR THE TREATMENT OF THE CONSEQUENCES OF ANTITUMOR DRUG EXTRAVASATION" [219].

3.7 Medical Nutrition Therapy

• To date, no reliable evidence has been obtained regarding the effect of dietary habits on the risk of developing ocular melanoma, melanoma of other sites, or the risk of recurrence or progression of this disease in individuals already diagnosed. In this regard, any changes in the patients' usual diet are not recommended unless dictated by the need to correct comorbid conditions or to manage or prevent complications of ongoing treatment (surgical, medical, or radiation) [220].

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

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

5.1. Prevention

Not developed.

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 ocular melanoma. The goals of patient monitoring should be considered the early detection of disease recurrence (especially distant metastases), early detection of second malignancies (in particular, new melanomas), as well as psychosocial support for patients.

Comment: the recommended dispensary follow-up schedule and the content of follow-up visits are given in Table 9. Risk factors for progression in uveal melanoma are presented in Table 10. If at least one adverse prognostic factor is present, the risk category increases. In cases where local treatment is performed without morphological verification of the diagnosis, one should be guided by the TNM UICC clinical stage (see also Tables 1-5) [41, 42, 92, 226, 227].

Table 9. Recommended schedule of examinations for a patient with a previously established diagnosis within the framework of dispensary follow-up, compiled based on the recommendations given in the "Diagnostics" section and on the risks of disease progression (see also Table A3-1).

Table 10. Risk factors for progression in uveal melanoma [41, 42, 92, 226, 227].

Comment: in the postoperative period, patients with localized uveal melanoma develop a radiation reaction manifested by tumor tissue edema, increased secondary retinal detachment, and a transient increase in intraocular pressure. Symptoms of the radiation reaction may periodically manifest throughout the year. Therefore, dynamic follow-up of patients with localized uveal melanoma is performed by an ophthalmologist for the prevention and treatment of the radiation reaction.

Comments: radiation therapy for UM leads to a number of adverse radiation effects (complications) that are observed both in the early (up to 6 months) and late (after 6 months) periods. Early complications after plaque brachytherapy include secondary hypertension, restricted ocular motility, intraocular hemorrhage, edema and hyperemia of the ocular mucosa and periorbital tissues, requiring timely detection and treatment. Late complications after plaque brachytherapy include radiation cataract, secondary glaucoma (including neovascular), hemophthalmitis, neuroretinopathy (up to optic nerve atrophy), post-radiation scleral changes (necrosis), and ocular subatrophy. Risk factors for late complications include a high scleral radiation dose, an irradiated scleral diameter of more than 14 mm, pre-equatorial and juxtapapillary tumor localization, and repeated eye-conserving treatments (TTT, brachytherapy). The attention of the outpatient ophthalmologist should be directed toward the early detection and management of these complications.

Comment: a prospective randomized clinical trial among patients with UM and a high risk of progression (N = 188) demonstrated that performing contrast-enhanced abdominal MRI every 6 months after primary local treatment by ophthalmologists detected asymptomatic metastatic liver disease in 50% of patients within the first year and a half after primary treatment (and 12 patients successfully underwent R0 resection of liver metastases as the sole manifestation of the disease, which was detected in a timely manner) [47, 228]. A study directly comparing contrast-enhanced abdominal MRI and whole-body FDG PET-CT demonstrated greater sensitivity of MRI (67% vs. 41%, p = 0.01) [47].

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:

1) in accordance with the regulations on the organization of medical care by types of medical care, approved by the authorized Federal Executive Authority;

2) in accordance with the procedures for the provision of medical care approved by the authorized federal executive body and mandatory within the territory of the Russian Federation for all medical organizations;

3) based on these clinical guidelines;

4) taking into account the standards of medical care approved by the authorized Federal Executive Authority.

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).

When an oncological disease is suspected or detected 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 a consultation with an ophthalmologist at ophthalmology departments specializing in the care of patients with ocular malignancies to receive primary specialized health care.

To rule out metastatic disease, the patient is referred for a consultation with an oncologist. In the absence of metastatic disease, the patient is referred for treatment to ophthalmology departments specializing in the care of patients with ocular malignancies. If metastatic disease is detected during the initial examination or during dynamic follow-up, the patient is referred to an oncologist.

Upon confirmation of metastasis, care is provided by an oncologist and other medical specialists at an outpatient oncological care center, or in a primary oncological office, primary oncological department, or the polyclinic department of an oncological dispensary.

When a localized (intraocular) form of uveal melanoma is suspected or detected, the patient is referred for consultation and treatment to an ophthalmologist due to the specialist's appropriate qualifications at an ophthalmology department specializing in the care of patients with ocular malignancies. When a generalized form of UM is suspected or detected in a patient, general practitioners, district general practitioners, general family physicians, medical specialists (ophthalmologists), and mid-level medical personnel shall refer the patient in the established manner for a consultation at an outpatient oncological care center, or at a primary oncological office or primary oncological department of a medical organization to receive primary specialized health care.

After the diagnosis of UM is established (by an ophthalmologist), the patient must be referred by the ophthalmologist (independently, without an additional visit by the patient to an oncologist) for an MRI (contrast-enhanced magnetic resonance imaging of the abdominal cavity), contrast-enhanced dynamic CT of the abdominal cavity, and CT of the chest cavity to rule out disease dissemination.

When a diagnosis of or suspicion for UM (intraocular form) is established in a region, the patient must be referred to an ophthalmologist due to the specialist's appropriate qualifications at an ophthalmology department specializing in the care of patients with ocular malignancies for diagnosis establishment (confirmation) and to determine the scope and nature of local treatment.

If dissemination of UM is detected (suspected) during the initial visit to a physician in the region, the patient is referred for an oncologist's consultation to clarify the nature of the process.

Upon completion of local treatment, the patient is referred for follow-up care to an ophthalmologist and an oncologist. Following local tumor treatment, the ophthalmologist examines the patient every 3 months during the first year, then once every 6 months for the subsequent 2 years, and then once a year in subsequent years for life if the disease course is recurrence-free.

A consultation at an outpatient oncological care center, primary oncological office, or primary oncological department of a medical organization must be conducted no later than 5 working days from the date of issuing the referral for consultation. If distant metastasis is suspected, the oncologist of the outpatient oncological care center (or the oncologist of the primary oncological office or primary oncological department in the absence of an outpatient oncological care center) arranges for the acquisition of biopsy (surgical) material and organizes other diagnostic tests necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

If distant metastasis is suspected and it is impossible to obtain biopsy (surgical) material or perform other diagnostic tests within the medical organization that houses the outpatient oncological care center (primary oncological office, primary oncological department), the attending physician refers the patient to an oncological dispensary or a medical organization providing medical care to patients with oncological diseases.

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

When an oncological disease is suspected and/or detected in a patient during the provision of emergency medical care, such patients are transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine management tactics and the need for additional specialized anti-tumor treatment methods. When a localized (intraocular) form of UM is suspected or detected, the patient is referred for consultation and treatment to an ophthalmologist at an ophthalmology department specializing in the care of patients with ocular malignancies.

The oncologist of an outpatient oncological care center (primary oncological office, primary oncological department), when intraocular melanoma is suspected, rules out tumor dissemination and refers the patient to an ophthalmologist at an ophthalmology department specializing in the care of patients with ocular malignancies.

The timeframe for initiating specialized, excluding high-tech, medical care for patients with cancer in a medical organization providing medical care to cancer patients must not exceed 14 calendar days from the date of histological verification or instrumental confirmation (for organ-sparing surgeries) of the malignant neoplasm, or 14 calendar days from the date of establishing a preliminary diagnosis of a malignant neoplasm (in the absence of medical indications for pathoanatomical examinations on an outpatient basis).

Specialized, including high-tech, medical care for uveal melanoma is provided by ophthalmologists specializing in the treatment of ocular oncology, and radiation therapists in an ophthalmology department specializing in the provision of care to patients with ocular tumors, possessing the license, required material and technical resources, and certified specialists, in inpatient and day-care settings, and includes prevention, diagnosis, and treatment of malignant tumors requiring special methods and complex unique medical technologies, as well as medical rehabilitation.

When a localized form of uveal melanoma is detected in a medical organization specializing in the provision of care to patients with ocular tumors, the management strategy for medical examination and treatment is determined by a concilium of oncologists, radiation therapists, and ophthalmologists, involving other medical specialists if necessary. The decision of the medical concilium is formalized in a protocol, signed by the participating physicians, and entered into the patient's medical documentation.

Specialized, including high-tech, medical care for metastatic uveal melanoma is provided by oncologists and radiation therapists in an oncology dispensary or in medical organizations providing care to cancer patients, possessing the license, required material and technical resources, and certified specialists, in inpatient and day-care settings, and includes prevention, diagnosis, and treatment of malignant tumors requiring special methods and complex unique medical technologies, as well as medical rehabilitation.

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

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

• presence of oncological disease complications requiring emergency and urgent specialized medical care;

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

Indications for elective hospitalization in a medical organization are:

• the need to perform complex interventional diagnostic medical interventions requiring subsequent monitoring in an inpatient or day-inpatient 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 specialized, including high-tech, medical care in a 24-hour inpatient or day-care setting in the absence of treatment complications requiring drug correction and/or medical interventions in an inpatient setting;

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

• the need to transfer the patient to another medical organization according to the relevant medical profile. The conclusion on the expediency of transferring the patient to a specialized medical organization is made after a preliminary consultation based on the provided medical documents and/or a preliminary examination of the patient by medical specialists of the 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;

• taking into account the rarity of this pathology, all cases of uveal melanoma are recommended to be referred for consultation in person or via telemedicine technologies to obtain a second opinion regarding further treatment tactics;

• 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

Table 11. Prognostic factors in uveal melanoma (UICC TNM 8th edition) [36].

Criteria for Evaluating the Quality of Medical Care

Criteria for assessing the quality of medical care are given in Table 12.

Table 12. Criteria for assessing the quality of medical care

References

Appendix A1. Working Group Composition

Working Group Moderator:

Samoilenko I.V., PhD in Medical Sciences, Senior Researcher at the Department of Skin Tumors, Drug Treatment Department, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health; Board Member of the Association of Melanoma Specialists.

Working Group

Section on the Treatment of Intraocular Melanoma and Medical Rehabilitation:

1. Amiryan A.G., Doctor of Medical Sciences, Associate Professor of the Department of Continuing Medical Education, Chief Researcher at the Department of Ocular Oncology and Radiology, National Medical Research Center of Eye Diseases named after Helmholtz of the Russian Ministry of Health.

2. Borodin Yu.I., PhD in Medical Sciences, Head of the Radiology Department, National Medical Research Center of Eye Diseases named after Helmholtz of the Russian Ministry of Health, Association of Ophthalmologists LLC.

3. Brovkina A.F., Academician of the RAS, Professor of the Department of Ophthalmology with a Course in Pediatric Ophthalmology and Ocular Oncology and Orbital Pathology, Russian Medical Academy of Continuing Professional Education of the Ministry of Health of the Russian Federation, Honored Scientist of the Russian Federation, Association of Ophthalmologists LLC.

4. Panova E.E., Doctor of Medical Sciences, Professor, Honored Physician of the Russian Federation, Deputy Director for Scientific Work, St. Petersburg Branch of the S.N. Fyodorov Eye Microsurgery Federal State Institution of the Russian Ministry of Health, Professor of the Department of Ophthalmology, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, Association of Ophthalmologists LLC.

5. Panteleeva O.G., Doctor of Medical Sciences, Associate Professor of the Department of Continuing Medical Education, Leading Researcher, Ophthalmologist at the Department of Ocular Oncology and Radiology, National Medical Research Center of Eye Diseases named after Helmholtz, Association of Ophthalmologists LLC.

6. Sahakyan S.V., Doctor of Medical Sciences, Professor, Honored Physician of Russia, Ophthalmologist, Oncologist at MirA Medical Center, Association of Ophthalmologists LLC.

7. Parmon Ya.V., PhD in Medical Sciences, Head of the Ophthalmic Department for the Treatment of Ocular Oncological Diseases, Ophthalmologist, Association of Ophthalmologists LLC.

8. Tsygankov A.Yu., PhD in Medical Sciences, Researcher, Ophthalmologist at the Department of Ocular Oncology and Radiology, National Medical Research Center of Eye Diseases named after Helmholtz, Association of Ophthalmologists LLC.

9. Yarovoy A.A., Doctor of Medical Sciences, Head of the Department of Ocular Oncology and Radiology, S.N. Fyodorov Eye Microsurgery Federal State Institution of the Russian Ministry of Health, Russian Ophthalmological Society.

10. Yarovaya V.A., PhD in Medical Sciences, Ophthalmologist at the Department of Ocular Oncology and Radiology, S.N. Fyodorov Eye Microsurgery Federal State Institution of the Russian Ministry of Health, Russian Ophthalmological Society.

Section on Dispensary Monitoring and Treatment of Metastatic and Unresectable Uveal Melanoma:

1. Demidov L.V., Doctor of Medical Sciences, Professor, Head of the Skin Tumors Oncology Department, Drug Treatment Department, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, Chairman of the Board of the Association of Melanoma Specialists.

2. Dolgushin B.I., Doctor of Medical Sciences, Professor, Academician of the RAS, Director of the Research Institute of Clinical and Experimental Radiology, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, President of the National Society of Interventional Oncoradiologists.

3. Zaretsky A.R., Head of the Oncology Direction, E.I. Schwartz Association of Specialists in Molecular Medicine, Laboratory and Clinical Genetics, 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, Senior Researcher at the Department of Molecular Technologies, Research Institute of Translational Medicine, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

4. Nazarova V.V., PhD in Medical Sciences, Oncologist at the Skin Tumors Oncology Department, Drug Treatment Department, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, Member of the Association of Melanoma Specialists.

5. Novik A.V., Doctor of Medical Sciences, Leading Researcher at the Research Department of Oncoimmunology, Oncologist at the Antitumor Drug Treatment Department, National Medical Research Center of Oncology named after N.P. Petrov of the Russian Ministry of Health, Associate Professor of the Department of Oncology, Pediatric Oncology and Radiation Therapy, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, Board Member of the Association of Melanoma Specialists.

6. Orlova K.V., PhD in Medical Sciences, Senior Researcher at the Skin Tumors Oncology Department, Drug Treatment Department, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, Board Member of the Association of Melanoma Specialists.

7. Samoilenko I.V., PhD in Medical Sciences, Senior Researcher at the Skin Tumors Oncology Department, Drug Treatment Department, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, Board Member of the Association of Melanoma Specialists.

8. Utyashev I.A., PhD in Medical Sciences, Melanoma, Skin Tumors and Sarcoma Team Leader at Hadassah Medical Moscow, Head of Clinical Research Department at Hadassah Clinic Moscow, Director of Clinical Research Department at Medscan Group of Companies.

9. Unguryan V.M., PhD in Medical Sciences, Chief Physician of the Kostroma Clinical Oncological Dispensary, Chief Freelance Oncologist of the Health Department of Kostroma Region.

Healthcare Organization Section:

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

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

3. Khaylova Zh.V., PhD in Medical Sciences, Chief Physician of the Clinic of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

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

5. Komarov Yu.I., PhD in Medical Sciences, Deputy Director for Organizational and Methodological Work, National Medical Research Center of Oncology named after N.P. Petrov of the Russian Ministry of Health.

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. ophthalmologists;

2. oncologists;

3. surgeons;

4. radiologists;

5. radiation therapists;

6. geneticists;

7. dermatovenereologists;

8. pathologists;

9. general physicians;

10. general practitioners (district physicians);

11. general practitioners (family physicians);

12. medical students, residents and postgraduate students;

13. clinical laboratory diagnosticians;

14. clinical laboratory diagnosticians.

Table 12. Scale for evaluating the levels of certainty of evidence for diagnostic methods (diagnostic interventions)

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

Table 14. Scale for evaluating the levels of recommendation grades for methods of prevention, diagnostics, treatment and rehabilitation (preventive, diagnostic, therapeutic, rehabilitation interventions)

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. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On Approval of the Procedure and Timelines for the Development of Clinical Practice Guidelines, Their Revision, the Standard Template of Clinical Practice Guidelines and Requirements for Their Structure, Composition and Scientific Validity of Information Included in Clinical Practice Guidelines" (registered with the Ministry of Justice of Russia on May 8, 2019, No. 54588).

7. Methodological recommendations for evaluating the scientific validity of information included in clinical practice guidelines, Center for Expertise and Quality Control of Medical Care of the Ministry of Health of the Russian Federation, 2019.

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

9. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services".

Table A3-1 shows the terms describing procedures in the clinical practice guideline and potential (closest) terms from the current nomenclature of medical services.

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

Appendix B. Physician Action Algorithms

Figure 1 Diagram of diagnosis and treatment for patients with intraocular uveal melanoma

Appendix C. Patient Information

Guidelines for self-skin examination and primary prevention of melanoma

Recommendations following local treatment for uveal melanoma.

• Lifelong follow-up by an ophthalmologist and an oncologist is required.

• Patient interaction with the attending physician is an essential component of care during the treatment process.

• Following organ-sparing treatment for uveal melanoma, physical exertion (sports, lifting weights over 5 kg) is strictly prohibited during the first 6 months after surgery.

• The patient must be trained in self-monitoring of visual functions (if vision is preserved after treatment) and be able to assess a decrease in vision.

• If eyelid swelling, eye redness, decreased vision, or eye pain occurs, consult an ophthalmologist immediately.

Recommendations for Chemotherapy Complications

In case of chemotherapy complications, you must contact your oncologist (chemotherapist).

1. If body temperature rises to +38 °C or higher, start systemic antibacterial drugs as prescribed by the 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 – CTLA4 and/or PD1 blockers (See Terms and Definitions)

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 treatment using CTLA4 and/or PD1 blockers (See "Terms and Definitions") are identified and treated at their very onset; this will help prevent them from progressing to more severe grades.

CTLA4 and/or PD1 monoclonal antibody blockers (See "Terms and Definitions") 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 side effects you might 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 (See "Terms and Definitions"). Early recognition of side effects allows your attending physician to promptly initiate appropriate therapy and prevent side effects from progressing to more severe grades.

If after treatment with CTLA4 and/or PD1 monoclonal antibody blockers (See "Terms and Definitions") 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:

• an increase in bowel movements to 2 or more times per day, or any nighttime diarrhea, any stool with 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 (body temperature rise 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 stool;

– painful;

– bloody;

– mucous.

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 CTLA4 and/or PD1 inhibitors (See "Terms and Definitions"). 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

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 [167].

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:

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

Appendix G2. Karnofsky Performance Scale

Russian name: Karnofsky scale.

Original title (if available): KARNOFSKY PERFORMANCE STATUS.

Source (official developer website, validated publication): Karnofsky D.A., Burchenal J.H.: 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 [229].

Type: rating scale.

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

Content (template):

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

Appendix G3. 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 website of the developers, validation publication):

Original publication: Eisenhauer E.A., Therasse P., Bogaerts J., Schwartz L.H., 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 recommendations No. 46 of the Scientific and Practical Center for Medical Radiology of the Moscow Healthcare Department [230].

Content:

1. Scope: although this guideline may be applicable to studies of malignant brain tumors, separate response evaluation criteria have also been published for this nosological category. This document is not intended for use in clinical trials involving malignant lymphomas, as separate international guidelines for response evaluation in lymphomas have been published.

2. It should also be noted that in routine clinical practice, oncologists frequently monitor malignancies 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 treating physician considers its use appropriate.

3. Assessment of tumor burden and measurability prior to systemic 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. Measurement specifications

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 have a caliper-measured diameter of ≥10 mm (e.g., cutaneous nodules). Color photographic documentation with a ruler for sizing is recommended. If a lesion is accessible both for clinical assessment and imaging, imaging is 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. To assess objective response to treatment or subsequent progression, it is necessary to determine the total tumor burden at baseline (pre-treatment), 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 present 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 designated as 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 taking into account:

• 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

4.3.2. Table G3-1. Evaluation of target lesions

4.3.2. Special notes on target lesion evaluation

• Lymph nodes: even if lymph nodes regress to < 10 mm (normal), their actual short axis measurement should be recorded at every assessment, even when complete response is achieved. Therefore, the sum of measurements may not equal 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

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,

• necessity of response confirmation (see section 4.6).

Table G3-3. Time-point response: patients with target (± non-target) lesions

Notations:

• CR — Complete Response

• PR — Partial Response

• SD — Stable Disease

• PD — Progressive Disease

• NE — Not Evaluable