Retinoblastoma: Clinical Guidelines

List of Abbreviations

⁹⁹Tc — technetium [99mTс] radiopharmaceutical (99m-pyrophosphate)

⁶⁷Ga — gallium [67Ga] citrate

auto-HSC — autologous hematopoietic stem cells

auto-HSCT — autologous hematopoietic stem cell transplantation

ALT — alanine aminotransferase

BT — brachytherapy

AST — aspartate aminotransferase

IOP — intraocular pressure

HIV — human immunodeficiency virus

IV — intravenous

HDCT — high-dose chemotherapy

G-CSF — granulocyte colony-stimulating factor

OD — optic disc

FU — follow-up

IVCT — intravitreal chemotherapy

CD — cryodestruction

CSI — craniospinal irradiation

LDH — lactate dehydrogenase

LOT — local ophthalmological therapy

LCT — local chemotherapy

HCF — healthcare facility

RT — external beam radiotherapy

ICD — International Classification of Diseases

MRI — magnetic resonance imaging

OS — overall survival

OCT — optical coherence tomography

BV — blood volume

CR — complete remission

CE — complete effect

CT — combination chemotherapy

RB — retinoblastoma

RLOI — retrolaminar optic nerve invasion

CT — X-ray computed tomography

SIAC — selective intra-arterial chemotherapy

ST — symptomatic treatment

TAD — total absorbed dose

TTT — transpupillary thermotherapy

US — ultrasound

ST — surgical treatment

CRA — central retinal artery

CNS — central nervous system

PR — partial remission

ALP — alkaline phosphatase

G — needle gauge unit

RB1 — retinoblastoma gene

Terms and Definitions

Relapse-free survival (RFS) — from the onset of remission until the occurrence of relapse.

Event-free survival (EFS) — from the start of treatment until the end of remission regardless of the cause.

Brachytherapy (BT) — local irradiation of the tumor using an ophthalmic applicator with a radioactive substance (strontium-90 or ruthenium-106).

Intravitreal chemotherapy (IVCT) — administration of a chemotherapeutic agent into the vitreous body.

Intraocular retinoblastoma — tumor involvement does not extend beyond the eye.

Cryodestruction (CD) — local destruction of the tumor using low temperatures.

Local ophthalmological therapy (LOT) — local methods of destroying an intraocular tumor.

Multimodal treatment — various methods of tumor management, chosen based on the following factors: stage of disease in each eye, age, heredity, histological criteria, and characteristics upon eye removal.

Overall survival (OS) — from the start of treatment until the end of the study or patient death.

Optical coherence tomography (OCT) — a non-invasive method for examining thin layers of skin, mucous membranes, as well as dental and ocular tissues, based on infrared radiation with a wavelength of about 1 µm to measure the delay of the beam reflected from the tissue.

Complete remission (CR) — absence of signs of tumor growth for 4 weeks after achieving a complete effect.

Complete effect (CE) — absence of tumor signs according to laboratory and instrumental diagnostic methods.

Progression — appearance of a new tumor lesion and/or growth of the primary tumor lesion or metastatic lesions by more than 25%.

Metastatic progression — metastasis of retinoblastoma to bones, bone marrow, lymph nodes, brain, and/or other organs outside the eyeball.

Local progression — appearance of a new tumor lesion(s) and/or growth of the primary tumor lesion(s) on the retina when local ophthalmological therapy methods (cryodestruction, laser therapy, brachytherapy) can be used as treatment.

Retinal progression — appearance of a new tumor lesion(s) and/or growth of the primary tumor lesion(s) on the retina when local ophthalmological therapy methods (cryodestruction, laser therapy, brachytherapy) cannot be used as treatment.

Vitreous progression — appearance of new tumor focus/foci and/or growth of existing tumor focus/foci in the vitreous body.

Progression extraocular — appearance of a new tumor lesion and/or growth of the primary tumor lesion involving the optic nerve and/or orbit.

Selective intraarterial chemotherapy (SICT) — infusion of a chemotherapeutic agent into the ophthalmic artery or collateral branches of the external carotid artery under hemodynamic blood flow redistribution.

Disease stabilization — absence of tumor growth on the retina and/or active tumor in the vitreous body, as well as no evidence of new foci.

Subretinal progression — appearance of a new tumor focus and/or growth of the primary tumor focus with extension into the subretinal space.

Type I tumor response to eye-sparing treatment — complete replacement of tumor foci with calcifications.

Type II tumor response to eye-sparing treatment — partial replacement of tumor foci with calcifications.

Type III tumor response to eye-sparing treatment — partial replacement of tumor foci with flat chorioretinal scars.

Type IV tumor response to eye-sparing treatment — complete replacement of tumor foci with flat chorioretinal scars or avascular linear white areas of gliosis.

Transpupillary thermotherapy (TTT) — local laser destruction of the tumor.

Partial remission (PR) — reduction in the size of tumor foci by more than 50% with no new lesions.

Orbital exenteration — surgical procedure in which the entire contents of the orbit are removed en bloc along with the tumor, eyelids, and periosteum lining the orbital walls.

Extraocular retinoblastoma — tumor involvement extends beyond the globe or metastases are present.

Enucleation of the eye — surgical procedure in which the eye is removed along with a segment of the optic nerve at least 15 mm long.

Electrophysiological study — a set of highly informative diagnostic methods for assessing the functions of the retina, optic nerve, visual pathways, and visual cortical areas. These methods are based on recording the electrical response to a specific light stimulus.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Retinoblastoma (RB) — a malignant tumor of the neural retina (inner lining of the eye), one of the most common malignant intraocular tumors in children [1,2].

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

RB is of neuroectodermal origin. There are two forms of the disease: hereditary and sporadic.

Hereditary RB is caused by a germline mutation in one allele of the RB1 gene, transmitted in an autosomal dominant manner with variable expressivity and incomplete penetrance, detected in 40% of cases [3,4]. Hereditary RB occurs in the majority of children with bilateral RB and in 15% of children with unilateral disease. Malignant cellular transformation requires a mutation of the second RB1 allele. This occurs in one or more retinal cells, but during the patient's life, other somatic cells can also be the target for a second mutation, increasing the risk of second malignant neoplasms such as osteosarcoma, breast cancer, small cell lung cancer, genitourinary cancers, and acute lymphoblastic leukemia [5,6].

Sporadic RB is caused by mutations in both alleles of the RB1 gene restricted to retinal cells and accounts for 60% of all cases, diagnosed at an older age as a unilateral monofocal tumor [5].

In rare cases, children with structural mutations in the RB1 gene may develop intracranial tumors, so-called trilateral RB, in which bilateral RB is combined with a pineal gland tumor (pineoblastoma) histologically similar to RB. In addition to the pineal region, the third tumor may also extend to midline brain structures.

Trilateral RB is detected in children in the first 4 years of life; signs of intracranial involvement may appear before visible ocular signs, simultaneously with ocular involvement, or after the detection of bilateral RB. The disease is identified in 5–10% of children with binocular RB, runs a severe clinical course, and has a high mortality rate [7].

Based on growth patterns, RB is classified into:

• Exophytic growth of RB. The tumor originates and grows between the outer retinal layers and the retinal pigment epithelium. As the tumor grows, a translucent cloud-like focus forms on the retina, which gradually enlarges into a smooth, white-gray nodule of uneven structure, detaching the retina. Further growth leads to a high subtotal retinal detachment reaching the lens, with a sharply protruding tumor nodule beneath its dome, often containing foci of dense white tissue — calcifications. On histological examination, a characteristic feature of exophytic growth is tumor invasion into the underlying choroid and extension beyond the globe.

• Endophytic growth of RB. The tumor spreads onto the inner surface of the retina and into the vitreous body. The tumor surface is tuberous, lobular in structure, permeated by newly formed blood vessels, and rapidly invades the vitreous body, forming multiple round, variously sized seeds that float in the vitreous like "stearic acid drops" — ranging from tiny pinpoint to clumpy masses. Sometimes part of the "tail" of the seeds is anchored to the retina. Thus, the main distinguishing feature of endophytic RB growth is the presence of vitreous seeds.

• Mixed growth of RB. The tumor combines features of the first two forms, characterized by the presence of tumor cell clones in the vitreous body and anterior chamber against the background of a dome-shaped retinal detachment.

• Diffuse growth of RB. The tumor infiltrates all retinal layers without forming large nodules or calcifications, invades the anterior segment of the eye, simulates inflammatory changes, and forms a pseudohypopyon.

Exophytic and mixed growth patterns are the most unfavorable for vital prognosis, whereas endophytic growth is the least favorable for eye-sparing treatment.

A distinctive feature of RB is the presence of multifocal retinal lesions, regardless of the tumor growth pattern. Multicentric RB is most frequently observed in bilateral cases.

Monocular RB most commonly develops in children under 3 years of age (90%). In older children, RB occurs in approximately 10% of cases. This group includes patients whose first symptoms appeared after 60 months of age. An important aspect for early detection is routine pediatric screening with mandatory ophthalmoscopy and pharmacological mydriasis every 3 months during the first year of life, and at least every 6 months thereafter.

The clinical course of RB in children older than 60 months is characterized by monocular involvement with reduced vision and strabismus. Anterior segment involvement predominates, featuring pseudoprecipitates and pseudohypopyon, along with secondary glaucoma and retinal detachment. Such a clinical picture is often misdiagnosed as uveitis, leading to unwarranted anti-inflammatory therapy, delaying specialized treatment, and significantly reducing the chances of preserving the patient's eye and life due to potential disease generalization [1,5,8].

1.3 Epidemiology of the Disease or Condition

The proportion of RB among all malignant tumors in children is 2.5–4.5%, and it accounts for 90–95% of all malignant intraocular tumors [2,9]. RB occurs with a frequency of 1 in 15,000–22,000 live births worldwide. In 80% of cases, the disease is diagnosed in children under 3–4 years of age [10]. Advanced stages are more common in unilateral cases, typically presenting as a solitary tumor focus. The peak incidence for unilateral RB is 24–29 months, and for bilateral RB, it is in the first year of life, with fellow eye involvement potentially developing metachronously.

Hereditary RB more frequently presents as a multifocal and/s or bilateral tumor and manifests at an earlier age — under 12 months [3-5,11].

1.4 Features of Coding the Disease or Condition

C69.2 — Malignant neoplasm of retina

1.5 Classification of the disease or condition

The International Classification of Retinoblastoma (ABC system) was proposed in Amsterdam in 2001 to determine the feasibility and types of eye-sparing treatment based on RB grouping, evaluating each eye separately in bilateral cases.

ABC Classification (Amsterdam, 2001):

Group A — small intraretinal tumors with a maximum dimension of 3 millimeters (mm) or less, located no closer than 1.5 mm from the optic disc and 3 mm from the fovea.

Group B — other discrete tumors confined to the retina, with tumor-associated subretinal fluid present less than 3 mm from the tumor base, without subretinal tumor seeding.

Group C — discrete focal tumors with local vitreous seeding over the tumor or subretinal seeding less than 3 mm from the tumor, with possible subretinal fluid greater than 3 mm and less than 6 mm from the tumor base.

Group D — diffusely spreading tumor with large tumor masses, multiple tumor seeds of varying sizes in the vitreous and/or subretinal space greater than 3 mm from the tumor, with subretinal fluid greater than 6 mm from the tumor base, up to total retinal detachment.

Group E — presence of any of the following poor prognostic factors: tumor touching the lens; tumor anterior to the anterior vitreous face, involving the ciliary body or anterior segment of the eye; diffuse infiltrative RB; neovascular glaucoma; vitreous opacity due to hemorrhage; tumor necrosis with aseptic orbital cellulitis; phthisis bulbi.

Patient staging is performed using the TNM classification [12].

TNM 8: Updated version of the TNM staging system for RB, developed by the American Joint Committee on Cancer (AJCC), 2018:

Clinical classification:

T — primary tumor:

cTx — primary tumor cannot be assessed;

cT0 — no evidence of primary tumor(s);

cT1 — intraocular tumor(s) confined to the retina with subretinal fluid level no more than 5 mm from the tumor base;

cT1a — tumor(s) less than or equal to 3 mm in diameter and located at least 1.5 mm away from the optic disc and fovea;

cT1b — tumor(s) greater than 3 mm in diameter or closer than 1.5 mm to the optic disc and fovea;

cT2 — intraocular tumor(s) with retinal detachment, vitreous seeding, or subretinal seeding;

cT2a — subretinal fluid level greater than 5 mm from the tumor base;

cT2b — tumor(s) with vitreous and/or subretinal seeding;

cT3 — advanced intraocular tumor(s);

cT3a — with ocular atrophy or subatrophy;

cT3b — with massive tumor extension to the pars plana, ciliary body, lens, iris, or anterior chamber;

cT3c — elevated intraocular pressure with neovascularization and/or development of buphthalmos;

cT3d — hyphema or massive vitreous hemorrhage;

cT3e — aseptic inflammation of the orbital soft tissues;

cT4 — extraocular tumor with extension into orbital tissues, including the optic nerve;

cT4a — involvement of the retrobulbar optic nerve, or its thickening along its course, or involvement of orbital tissues confirmed by imaging studies;

cT4b — extraocular tumor with clinically proven proptosis and an orbital mass.

N — regional lymph nodes:

cNx — regional lymph nodes cannot be assessed;

cN0 — no regional lymph node metastasis;

cN1 — proven metastatic involvement of preauricular, submandibular, and cervical lymph nodes.

M — distant metastasis:

cM0 — no signs or symptoms of intracranial or other distant metastasis;

cM1 — distant metastasis without histological confirmation;

cM1a — distant metastasis (e.g., involving bones, liver) confirmed clinically or by imaging studies;

cM1b — tumor involving the central nervous system according to imaging studies (exception: trilateral RB).

Pathomorphological classification pT:

pTx — intraocular tumor cannot be assessed;

pT0 — no intraocular tumor found;

pT1 — intraocular tumor confined to the retina, without local invasion, no optic nerve or choroidal involvement;

pT2 — intraocular tumor with local invasion:

pT2a — local choroidal invasion and pre- or intralaminar optic nerve invasion;

pT2b — tumor invasion of the iris stroma, trabecular meshwork, or Schlemm's canal;

pT3 — intraocular tumor with significant local invasion:

pT3a — massive choroidal invasion (> 3 mm in greatest dimension or multiple choroidal tumor foci totaling > 3 mm, or full-thickness choroidal invasion);

pT3b — tumor extension along the optic nerve past the lamina cribrosa, but not involving the resection margin;

pT3c — partial scleral invasion up to 2/3 of its thickness;

pT3d — invasion of the outer third of the sclera or invasion in or around emissary vessels;

pT4 — tumor extending beyond the eye: optic nerve involvement including the resection margin; tumor in the meningeal space around the optic nerve; full-thickness scleral invasion with extension to the episclera, invasion of peribulbar tissues, extraocular muscles, orbital bones, conjunctiva, and eyelids.

N — regional lymph nodes:

pNx — regional lymph nodes cannot be assessed;

pN0 — no regional lymph node metastasis;

pN1 — lymph nodes not involved.

M — distant metastasis:

pM1 — histologically confirmed distant metastases;

pM1a — all histologically confirmed distant metastases;

pM1b — histological confirmation of tumor presence in the CNS parenchyma or cerebrospinal fluid.

H — genetic features:

Hx — unknown or insufficient data to assess RB1 gene mutation;

H0 — absence of RB1 gene mutations confirmed by high-sensitivity molecular genetic blood testing;

H1 — bilateral RB, RB with intracranial primitive neuroectodermal tumor of the CNS (including trilateral RB), patient with familial RB, or RB1 gene mutation confirmed by high-sensitivity molecular genetic blood testing.

1.6 Clinical presentation of the disease or condition

The disease is often asymptomatic and manifests when the tumor spreads to the central retina or increases in size, affecting vision. An early symptom of tumor development when localized in the central retina may be strabismus. The most common symptom of the late stage of the disease is pupillary reflex whitening — leukocoria or the "cat's eye" reflex, which results from light reflection off the surface of the tumor lesion. In addition, late symptoms of the disease include: paralytic mydriasis (persistent pupillary dilation and lack of light reaction) resulting from secondary retinal detachment; hemophthalmos — vitreous hemorrhage; for tumors extending to the anterior vitreous, rubeosis iridis (pathological vessel growth — neovascularization — on the iris and in the angle of the anterior chamber — the space between the cornea and iris), where the retina experiences oxygen deprivation, leading to the formation of abnormal vessels. The newly formed vessels block the outflow of aqueous humor from the eye, causing an increase in intraocular pressure (IOP), which leads to the development of secondary neovascular glaucoma, and, consequently, enlargement of the eye — buphthalmos, accompanied by redness and eye pain, pseudohypopyon sign, and exophthalmos if the tumor invades the orbit [1,9,11,13].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Differential diagnosis of RB includes anterior and posterior uveitis of various etiologies, Coats disease, congenital cataracts, retinopathy of prematurity and retinal detachment, glaucoma, vitreous cysts, hemophthalmos, medullated nerve fibers, optic disc coloboma, and optic nerve glioma.

As a rule, an erroneous diagnosis of uveitis is made in cases of endophytic and mixed tumor growth patterns, when tumor seeds in the vitreous body or anterior chamber are interpreted as inflammatory precipitates. The presence of retinal hemorrhages or calcification within the lesion in 15–20% of cases may lead to a late-stage diagnosis of Coats' disease. Diagnoses of retinal detachment, retinopathy of prematurity, and cataract are typically made in cases of exophytic RB growth.

2.1 Complaints and Anamnesis

Comments: the course of pregnancy, childbirth, the newborn's health status, and potential residency of family members in ecologically unfavorable areas are clarified.

Comments: it is necessary to establish the characteristic clinical signs of retinoblastoma; a detailed description is provided in Section 1.6 "Clinical Presentation".

2.2 Physical Examination

2.3 Laboratory Diagnostics

2.4 Instrumental Diagnostics

Comment: including before the start of each course of chemotherapy and radiation therapy.

• OCT is recommended for patients with group A and B RB with a thickness of up to 3 mm and a postequatorial location to confirm the diagnosis, perform differential diagnosis of other retinal pathological processes, determine the formation of a chorioretinal scar, and detect ongoing or occult RB growth [20].

GCP CLE 4Grade of Recommendation C (Level of Evidence 4)

• Electrophysiological methods, including electroretinography and recording of visual evoked potentials of the cerebral cortex, are recommended for use in RB patients to assess the functions of the retina, optic nerve, and visual cortical areas following organ-preserving treatment [21].

Level of Evidence CGrade of Recommendation 4Level of Recommendation C (level of evidence 4)

Comment: MRI is recommended to be performed once every 6 months for 5 years from the moment remission is achieved [22].

2.5 Other Procedures

Comments: comprehensive molecular genetic examination includes: targeted high-throughput parallel DNA sequencing methods to search for point mutations and short insertions/deletions; multiplex ligation-dependent probe amplification (MLPA) to detect large deletions in the RB1 gene.

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

Treatment tactics depend on the patient's age, disease stage, tumor size and location, tumor growth pattern, presence of unilateral or bilateral involvement, secondary complications of the tumor process (atrophy or subatrophy of the eye, cataract, elevated intraocular pressure with iris neovascularization and/or development of buphthalmos, hyphema, hemophthalmos, pseudohypopyon), and heredity.

RB treatment must be multidisciplinary: to decide on prescribing chemotherapy, the patient must be consulted by a pediatric oncologist, while decisions regarding transpupillary thermotherapy or cryodestruction require an ophthalmologist's consultation. Decisions on prescribing and administering brachytherapy require consultations with both an ophthalmologist and a radiation oncologist, whereas radiation therapy requires a radiation oncologist.

Treatment strategy is determined by a multidisciplinary medical board.

3.1 Organ-sparing treatment of intraocular retinoblastoma

• Patients with group A intraocular RB are recommended local ophthalmic therapy (LOT) to destroy the intraocular tumor [27,28].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: polychemotherapy (PCT) is not recommended for this category of patients. LOT methods (cryotherapy, thermotherapy, laser therapy) are effective in treating patients with small tumors, but less effective in treating advanced processes.

Comments: this group includes patients with unilateral RB — group B tumor(s) in one eye; bilateral RB — group B tumor(s) in both eyes; bilateral RB — group A tumor in one eye and group B tumor(s) in the other eye; bilateral RB — group E tumor in the enucleated eye and group B tumor(s) in the remaining eye at the time of enucleation of the more affected eye with standard-risk histological factors. It is recommended to coordinate the administration of systemic chemotherapy with a pediatric oncologist at a pediatric oncology clinic.

Two-drug systemic chemotherapy (duration of 1 cycle is 21 days) [31]:

• #vincristine** — 1.5 mg/m² IV on day 1;

• #carboplatin** — 560 mg/m² IV on day 1.

For patients under 36 months of age, the dose is calculated per kg of body weight: #vincristine** — 0.05 mg/kg, #carboplatin **— 18.6 mg/kg,

To assess the response to systemic chemotherapy, patients undergo ophthalmoscopy after 2 courses of chemotherapy according to the regimen described above without additional local treatment, repeating at least every 2 courses of treatment. A total of up to 6 courses are prescribed. Starting from the 2nd course, systemic chemotherapy after the 2nd course is combined with additional local treatment. Local treatment (cryotherapy, laser therapy, brachytherapy) is performed in oncological ophthalmology departments [29].

For primary selective intra-arterial chemotherapy (SIAC), 3 to 5 mg of #melphalan** is used for each eye in age-appropriate doses [30,32].

• In patients with no regression or with intraocular tumor progression during treatment, it is recommended to alternate local chemotherapy with local treatment [34].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

• In patients with ongoing intraocular tumor progression after systemic chemotherapy, local chemotherapy, and local treatment that precludes the repeated use of eye-conserving treatments due to the risk of extraocular tumor spread, standard treatment including enucleation of the eye is recommended [34-36].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: these groups include patients with unilateral and bilateral RB who have, in at least one eye, tumor spread consistent with the classification for groups C or D, confirmed during an ophthalmological examination performed no later than three weeks prior to enrollment in the study. Patients may undergo enucleation of one eye if the tumor in the second eye shows spread characteristic of groups C or D, provided there is no history of prior chemotherapy or radiation therapy. Treatment is indicated for patients who have pathomorphological criteria of standard and intermediate risk in the enucleated eye.

Three-drug systemic chemotherapy [7]:

• #vincristine** — 1.5 mg/m² IV on day 1;

• #etoposide** — 150 mg/m² IV on days 1 and 2;

• #carboplatin** — 560 mg/m² IV on day 1.

For patients under 36 months of age, the dose is calculated per kg of body weight: #vincristine** — 0.05 mg/kg, #carboplatin **— 18.6 mg/kg, #etoposide** — 5 mg/kg.

Local treatments may be performed for the first time after the completion of the 2nd course of systemic chemotherapy (from day 21 to day 28) prior to local chemotherapy. From the 2nd to the 4th courses of systemic chemotherapy combined with local chemotherapy, local treatment is performed before local chemotherapy.

Brachytherapy and cryotherapy must not be performed simultaneously with selective intra-arterial chemotherapy (SIAC), nor less than 1 month before or after SIAC. For primary SIAC without the use of three-drug chemotherapy, 3 to 5 mg of #melphalan** is used for each eye depending on age [30,32].

The SIAC procedure must be performed in a federal-level medical institution in the interventional radiology operating room using modern anesthetic support, no earlier than 21 days and no later than 28 days from the start of the previous polychemotherapy course. Laser treatment may be combined with local chemotherapy. If necessary, local treatment and local chemotherapy are repeated.

Comments: the drugs listed below are used in the practice of treating patients with RB.

Second-line chemotherapy:

• #ifosfamide** 1.8 g/m² (for body weight up to 12 kg — 60 mg/kg) IV on days 1, 2, 3, 4, and 5;

• doxorubicin** 20 mg/m² (for body weight up to 12 kg — 1 mg/kg) IV on days 2 and 4;

• #vincristine ** 1.5 mg/m² (under 36 months of age — 0.05 mg/kg) IV on days 1, 8, and 15.

• Selective intra-arterial chemotherapy (SIAC) as part of three-drug chemotherapy is recommended to be performed no earlier than after 1 course of systemic chemotherapy [37].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

Comment: SIAC minimizes the systemic impact of chemotherapy on the body while achieving a high concentration of chemotherapeutic agents in the tumor.

Comments: for refractory and relapsed intraocular RB, SIAC utilizes two or more chemotherapeutic agents (#melphalan**, #topotecan**, #carboplatin**)

— in the absence of secondary complications of the tumor process: atrophy or phthisis bulbi; cataract; elevated intraocular pressure with iris neovascularization and/or buphthalmos development; hyphema; hemophthalmus; pseudohypopyon.

In each case, the feasibility of SIAC is determined after consultation with an ophthalmologist and pediatric oncologist; the technique for delivering the chemotherapeutic agent to the tumor is determined by an interventional radiologist.

There are two techniques for performing SIAC:

1. Microcatheter technique — superselective catheterization using a microcatheter of the ophthalmic artery/collateral branches of the external carotid artery under hemodynamic blood flow redistribution;

2. Microballoon technique — temporary cessation of blood flow in the internal carotid artery basin distal to the origin of the ophthalmic (left or right) artery using a special intravascular occluder, with administration of the chemotherapeutic agent proximal to the occluder.

• Intravitreal chemotherapy (IVCT) is recommended for endofytic and mixed tumor growth patterns, with vitreous seeds, as well as when new retinal foci and vitreous seeds appear during and at the end of treatment [37,47,48].

GCP CLE 4Grade of Recommendation C (Level of Evidence 4)

Comments: IVCT — the injection of a chemotherapeutic agent into the vitreous body is performed in a federal-level medical institution in the operating room of an ocular oncology department. Complications: chorioretinal dystrophy of varying severity up to atrophy, annular opacification of the posterior lens capsule, decreased visual acuity.

3.2 Treatment of children with unilateral retinoblastoma after primary enucleation

Comments: Table 1. Histological criteria and their characteristics

• If standard-risk histological factors are identified, lifetime follow-up is recommended [37].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

Comments: adjuvant chemotherapy is not indicated for standard risk.

• Patients in the intermediate-risk group with tumor invasion of the anterior chamber of the eye, iris, ciliary body, massive choroidal invasion, intra- and retrolaminar optic nerve tumor invasion are recommended 6 cycles of adjuvant chemotherapy [51].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

Comments: the following drugs are used: #vincristine** (1.5 mg/m² (maximum 2 mg), day 1), #etoposide** (150 mg/m², days 1, 2), and #carboplatin** (560 mg/m², day 1), with a 21-day cycle. For patients under 36 months of age, the dose is calculated per kg of body weight: #vincristine** — 0.05 mg/kg, #carboplatin **— 18.6 mg/kg, #etoposide** — 5 mg/kg.

Comments: chemotherapy regimen for the high-risk group [16,23,56]:

1. cyclophosphamide** 400 mg/m²/day (for weight up to 12 kg — 13 mg/kg body weight), days 1–5, IV drip in 200 ml of 0.9% sodium chloride** solution over 1 hour;

2. #carboplatin** 500 mg/m²/day (for weight up to 12 kg — 12 mg/kg body weight), day 5, IV drip in 400 ml of 0.9% sodium chloride** solution over 6 hours;

3. #etoposide** 100 mg/m²/day (for weight up to 12 kg — 3.3 mg/kg body weight), days 1–5, IV drip in 200 ml of 0.9% sodium chloride** solution or 5% dextrose** solution over 1 hour;

4. mesna** — 400 mg/m²/day, days 1–5, IV drip.

Each chemotherapy cycle must begin no later than 21–28 days from the start of the previous one.

Prechiasmatic optic nerve resection should be performed in a federal-level medical institution within a neuro-oncology department.

At the start of each subsequent chemotherapy course, the complete blood count should show a leukocyte count of > 2.0 × 10⁹/L and a platelet count of > 75 × 10⁹/L. If the platelet or leukocyte count is lower, the start of the next chemotherapy course is postponed until blood counts recover.

3.3 High-dose chemotherapy with autologous hematopoietic stem cell transplantation

3.4 Surgical treatment

Comments: the absence of extraocular tumor spread beyond the eye, including along the orbital and/or intracranial parts of the optic nerve, must be confirmed by contrast-enhanced MRI of the orbits and brain prior to surgery.

• The presence of buphthalmos in intraocular retinoblastoma suggests two to three courses of chemotherapy with the following drugs: #vincristine** (1.5 mg/m² (maximum 2 mg), day 1), #etoposide** (150 mg/m², days 1, 2), and #carboplatin** (560 mg/m², day 1), 21-day cycle. For patients under 36 months of age, the dose is calculated per 1 kg of body weight: #vincristine** — 0.05 mg/kg, #carboplatin** — 18.6 mg/kg, #etoposide** — 5 mg/kg prior to planned enucleation, followed by adjuvant chemotherapy to complete a total of six courses, regardless of identified histological criteria and their characteristics. Prechiasmatic optic nerve resection is recommended: when tumor cells are present at the resection margin of the optic nerve following primary enucleation in patients with intraocular retinoblastoma; in case of tumor infiltration along the entire length of the orbital and/or intracranial part of the optic nerve up to the chiasm, as shown by contrast-enhanced MRI [62].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

Comments: this type of surgery involves transection of the optic nerve at the chiasm to remove its intracranial and intraorbital portions and must be performed after preliminary chemotherapy within a neuro-oncology department of a federal-level medical institution.

• Transpupillary thermotherapy (thermotherapy of retinal and choroidal neoplasms, A22.26.015) is a type of laser treatment that is recommended for tumor thickness not exceeding 3.0 mm, including multifocal growth patterns [8,11,28,56].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

• Cryodestruction — the application of low temperatures (cold) to the retinoblastoma focus — is recommended for pre-equatorial tumor localization with a thickness of no more than 4 mm [8,11,28,56].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

• Brachytherapy — local irradiation of the tumor by suturing a radioactive ophthalmic applicator (strontium-90, ruthenium-106) to the sclera — is recommended for tumor thickness not exceeding 6 mm [8,11,28,56].

GCP CLE 4Grade of Recommendation C (Level of Evidence 4)

Comment: the radiation dose to the apex of the tumor using ruthenium-106 should be at least 80–90 Gy, and using strontium-90 (strontium-96) — at least 120 Gy.

3.5 External beam radiotherapy (EBRT)

• RT is recommended for patients if retrolaminar tumor invasion of the optic nerve, extrascleral tumor extension, and/or the presence of tumor cells at the resection margin of the optic nerve are detected after eye enucleation [27,63].

GCR CLeE 4Grade of Recommendation C (Level of Evidence 4)

Comments: radiation therapy to the orbit is performed within periods not exceeding 1 month after surgical treatment. It is advisable to use photon irradiation with linear accelerators (6 MeV) or proton therapy.

Recommended radiation doses: for patients from intermediate-risk groups with retrolaminar tumor growth and high-risk groups, RT to the orbit is performed within no more than 1 month after surgical treatment, using 25 daily fractions with a fraction dose (FD) of 2 Gy, 5 times a week, resulting in a total tumor dose (TTD) of 50 Gy.

• RT is recommended for patients when radical surgery to remove the primary eye tumor is impossible, in case of CNS metastatic involvement, and in trilateral retinoblastoma [64,65].

GCR CLeE 4Grade of Recommendation C (Level of Evidence 4)

Comments: it is advisable to use photon irradiation with linear accelerators (6 MeV) or proton irradiation. RT is performed at the final stage after CHT in the volume of craniospinal irradiation (CSI) with inclusion of the affected orbit in case of an unresectable primary eye tumor, followed by a boost to the primary site and metastatic lesions in the CNS. In trilateral RB, after the CHT stage, CSI is performed followed by a boost to the pineoblastoma. During CSI: FD — 1.8 Gy, for children under 60 months — CSI TTD 23.4 Gy, for children over 60 months — 36.0 Gy, followed by a boost to metastatic lesions in the spinal cord up to a TTD of 50.4 Gy, and metastatic lesions in the brain and affected orbit up to a TTD of 54.0 Gy.

• RT is recommended for patients with metastatic involvement of preauricular lymph nodes, as well as with bone, soft tissue, salivary gland, or other localization metastases [66,67].

GCP CLE 4Grade of Recommendation C (Level of Evidence 4)

Comments: it is advisable to use photon irradiation with linear accelerators (6 MeV) or proton irradiation. For regional metastasis zones, RT is performed simultaneously and/or sequentially with the treatment of the primary tumor spread zone in the orbit. For distant metastatic sites (up to 5 sites), RT is performed after the radiation oncologist assesses the priority of irradiating these zones in the context of comprehensive treatment; it can be performed at a later date and must take into account factors such as the safety of radiotherapy, response to chemotherapy, symptomatic manifestation, and the safety of the lesions in case of their progression. Patients receive a radical dose to the affected lymph nodes and distant metastasis areas with an FD of 2.0 Gy up to a TTD of 50.0 Gy.

3.6 Supportive care

Comments: ondansetron** is effective when administered at a dose of 0.15 mg/kg 30–60 minutes before the start of systemic chemotherapy. For moderate emetogenic chemotherapy, it needs to be administered three times a day in children over 1 month of age.

Comments: provided that leukocyte filters are used or platelet concentrate is obtained using separators equipped with leukocyte filters or traps, blood component irradiation may be omitted. Transfusion of blood components is performed without regard to the cytomegalovirus status of donors and recipients.

Comments: the volume of infusion therapy during chemotherapy and within 2–4 days after its completion should be evenly distributed over 24 hours and maintained at 3 L/m²/day. If necessary, furosemide or other diuretics are prescribed in standard doses. In case of mild intoxication and a stable patient condition, the volume can be subsequently reduced to 2–2.5 L/m²/day.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

Follow-up examinations after achieving remission in patients with intraocular unilateral RB after enucleation:

* as clinically indicated

Follow-up examinations after achieving remission in patients with intraocular RB after eye-sparing treatment:

* as clinically indicated

Follow-up examinations after achieving remission in patients with extraocular RB:

*as clinically indicated

6. Organization of Medical Care

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

1) presence of RB complications requiring specialized medical care in an emergency and urgent form;

2) presence of treatment complications (surgical intervention, radiation therapy, drug therapy, etc.).

Indications for hospitalization in a medical organization in a planned form are:

1) necessity of specialized antitumor treatment (surgical intervention, radiation therapy, drug therapy).

Indications for discharging a patient from a medical organization are:

1) completion of the course of treatment or one of the stages of specialized, including high-tech, medical care in a 24-hour inpatient unit or day hospital, provided there are no treatment complications requiring drug correction and/or medical interventions in an inpatient setting;

2) refusal by the patient or their legal representative of specialized, including high-tech, medical care in a 24-hour inpatient unit or day hospital prescribed by the medical council of the oncological 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;

3) the need to transfer the patient to another medical organization in the relevant medical care profile. The conclusion on the feasibility of transferring the patient to a specialized medical organization is made after a preliminary consultation based on the provided medical documents and/or preliminary examination data by specialists of the medical organization to which the transfer is planned.

7. Additional Information

Adverse factors affecting treatment outcomes:

1. Development of infectious complications;

2. Development of anemia, thrombocytopenia syndromes requiring blood component transfusions;

3. Prolongation of intervals between chemotherapy administrations;

4. Dose reductions of chemotherapeutic agents;

5. Violation of the patient monitoring schedule both during treatment and during follow-up.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Borodin Yuri Ivanovich, PhD (Medicine), Head of the Radiology Department, National Medical Research Center for Eye Diseases named after Helmholtz of the Russian Ministry of Health, member of the Association of Ophthalmologists.

2. Varfolomeeva Svetlana Rafaelevna, MD, Professor, Director of the Research Institute of Pediatric Oncology and Hematology named after Academician of the RAMS L.A. Durnov, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, President of the Russian Society of Pediatric Oncologists and Hematologists (RSPOH).

3. Volodin Denis Pavlovich, PhD (Medicine), postgraduate physician at the Department of Ocular Oncology and Radiology, S.N. Fyodorov Eye Microsurgery Federal State Institution of the Russian Ministry of Health, member of the National Non-Governmental Organization "Society of Ophthalmologists of Russia".

4. Grigorenko Vasily Andreevich, Radiation Oncologist, Head of the Radiotherapy Department, Research Institute of Pediatric Oncology and Hematology named after Academician of the RAMS L.A. Durnov, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, full member of the Moscow Society of Radiation Therapists (MSRT), Paediatric Radiation Oncology Society (PROS), and Russian Association of Therapeutic Radiation Oncologists (RATRO).

5. Gorovtsova Olga Valerievna, Ophthalmologist at the Pediatric Oncology Department of Surgical Treatment Methods with Chemotherapy No. 1 (Head and Neck Tumors), Research Institute of Pediatric Oncology and Hematology named after Academician of the RAMS L.A. Durnov, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, member of the Russian Society of Pediatric Oncologists and Hematologists (RSPOH).

6. Zhiltsova Marina Georgievna, PhD (Biology), Senior Researcher at the Clinical Laboratory, National Medical Research Center for Eye Diseases named after Helmholtz of the Russian Ministry of Health, member of the Association of Clinical Cytologists of Russia (ACCR) and the Russian Society of Oncopathologists.

7. Ivanova Olga Andreevna, PhD (Medicine), Ophthalmologist at the Department of Ocular Oncology, National Medical Research Center for Eye Diseases named after Helmholtz of the Russian Ministry of Health, member of the Association of Ophthalmologists.

8. Katargina Lyudmila Anatolyevna, MD, Professor, Honored Doctor of the Russian Federation, Chief freelance pediatric ophthalmologist of the Russian Ministry of Health, Deputy Director for Research, Head of the Department of Eye Pathology in Children, National Medical Research Center for Eye Diseases named after Helmholtz of the Russian Ministry of Health, member of the Association of Ophthalmologists.

9. Kazantsev Ilya Viktorovich, PhD (Medicine), Head of the Pediatric Bone Marrow Transplantation Department No. 2, R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Associate Professor at the Department of Hematology, Transfusiology and Transplantology named after Prof. B.V. Afanasyev, Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health, St. Petersburg.

10. Kirgizov Kirill Igorevich, PhD (Medicine), Deputy Director for Research, Head of the Department of Pediatric Bone Marrow and Hematopoietic Stem Cell Transplantation, Research Institute of Pediatric Oncology and Hematology named after Academician of the RAMS L.A. Durnov, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

11. Kotelnikova Anastasia Viktorovna, PhD (Medicine), Ophthalmologist at the Department of Ocular Oncology and Radiology, S.N. Fyodorov Eye Microsurgery Federal State Institution of the Russian Ministry of Health, member of the National Non-Governmental Organization "Society of Ophthalmologists of Russia".

12. Kyun Yulia Aleksandrovna, Ophthalmologist at the Outpatient Department, Research Institute of Pediatric Oncology and Hematology named after Academician of the RAMS L.A. Durnov, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

13. Zelenova Ekaterina Evgenyevna, Geneticist at the Outpatient Department, Research Institute of Pediatric Oncology and Hematology named after Academician of the RAMS L.A. Durnov, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, Senior Laboratory Assistant at the Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, member of the Moscow Society of Medical Geneticists.

14. Malakhova Alina Anatolyevna, Head of the Organizational and Methodological Department with Cancer Registry and Medical Archive, Research Institute of Pediatric Oncology and Hematology named after Academician of the RAMS L.A. Durnov, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, member of the Russian Society of Pediatric Oncologists and Hematologists (RSPOH).

15. Moroz Ekaterina Anatolyevna, PhD (Medicine), Pathologist at the Pathological Anatomy Department of the CDC, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, member of the Russian Division of the International Academy of Pathology / Russian Society of Pathologists.

16. Myakoshina Elena Borisovna, MD, Senior Researcher at the Department of Ocular Oncology and Radiology, National Medical Research Center for Eye Diseases named after Helmholtz of the Russian Ministry of Health, member of the Association of Ophthalmologists.

17. Panteleeva Olga Gennadievna, MD, Leading Researcher at the Department of Ocular Oncology and Radiology, National Medical Research Center for Eye Diseases named after Helmholtz of the Russian Ministry of Health, member of the Association of Ophthalmologists.

18. Pogrebnyakov Igor Vladimirovich, PhD (Medicine), Endovascular Diagnostics and Treatment Surgeon, Head of the Department of X-ray Surgical Diagnostic and Treatment Methods, Department of Interventional Radiology, Research Institute of Clinical and Experimental Radiology, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, member of the Society of Interventional Oncoradiologists of Russia, member of the European Society of Radiology (ESR).

19. Polyakov Vladimir Georgievich, MD, Professor, Academician of the RAS, Head of the Pediatric Oncology Department of Surgical Treatment Methods with Chemotherapy No. 1 (Head and Neck Tumors), Advisor to the Director of the Research Institute of Pediatric Oncology and Hematology named after Academician of the RAMS L.A. Durnov, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, Head of the Department of Pediatric Oncology named after Academician L.A. Durnov, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, member of the Russian Society of Pediatric Oncologists and Hematologists (RSPOH), member of the International Society of Paediatric Oncology (SIOP).

20. Saakyan Svetlana Vagovna, MD, Professor, Corresponding Member of the RAS, Head of the Department of Ocular Oncology and Radiology, Helmholtz National Medical Research Center of Eye Diseases of the Russian Ministry of Health, member of the Association of Ophthalmologists, full member of the International Society of Ocular Oncology (ISOO).

21. Serov Yuri Aleksandrovich, Ophthalmologist at the Pediatric Oncology Department of Surgical Treatment Methods with Chemotherapy No. 1 (Head and Neck Tumors), Research Institute of Pediatric Oncology and Hematology named after Academician of the RAMS L.A. Durnov, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, member of the Russian Society of Pediatric Oncologists and Hematologists (RSPOH).

22. Tatskov Robert Aleksandrovich, PhD (Medicine), Ophthalmologist at the Department of Ocular Oncology and Radiology, Head of the Operating Theater, National Medical Research Center for Eye Diseases named after Helmholtz of the Russian Ministry of Health, member of the Association of Ophthalmologists.

23. Ushakova Tatyana Leonidovna, MD, Leading Researcher at the Pediatric Oncology Department of Surgical Treatment Methods with Chemotherapy No. 1 (Head and Neck Tumors), Research Institute of Pediatric Oncology and Hematology named after Academician of the RAMS L.A. Durnov, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, member of the Russian Society of Pediatric Oncologists and Hematologists (RSPOH), Professor at the Department of Pediatric Oncology named after Academician L.A. Durnov, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, full member of the International Society of Ocular Oncology (ISOO) and the International Society of Paediatric Oncology (SIOP).

24. Tsygankov Aleksandr Yuryevich, PhD (Medicine), Researcher at the Department of Ocular Oncology and Radiology, National Medical Research Center for Eye Diseases named after Helmholtz of the Russian Ministry of Health.

25. Shatskikh Anna Viktorovna, PhD (Medicine), Head of the Pathological Anatomy Department, S.N. Fyodorov Eye Microsurgery Federal State Institution of the Russian Ministry of Health.

26. Olga V. Yugay, Ophthalmologist at the Polyclinic Department of the Research Institute of Pediatric Oncology and Hematology named after Academician of the RAMS L.A. Durnov, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

27. Vera A. Yarovaya, PhD in Medicine, Ophthalmologist-ophthalmologist at the Department of Ocular Oncology and Radiology, National Medical Research Center "S.N. Fyodorov Eye Microsurgery Federal State Institution" of the Russian Ministry of Health, Full Member of the International Society of Ocular Oncology (ISOO).

28. Andrey A. Yarovoy, MD, DSc, Head of the Department of Ocular Oncology and Radiology, National Medical Research Center "S.N. Fyodorov Eye Microsurgery Federal State Institution" of the Russian Ministry of Health, Member of the All-Russian Public Organization "Russian Ophthalmological Society", Full Member of the International Society of Ocular Oncology (ISOO).

No conflict of interest is declared.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Ophthalmologists;

2. Pediatric oncologists;

3. Cardiovascular surgeons and interventional radiologists;

4. Radiologists;

5. Medical geneticists;

6. Radiation therapists;

7. Pediatricians;

8. Medical students, residents, and postgraduate students.

Methods used for evidence collection/selection: electronic database searches; analysis of current scientific developments on the problem of RB in Russia and abroad; synthesis of the practical experience of Russian and international specialists.

Table A2.1. Levels of Evidence (LE) rating scale for diagnostic methods (diagnostic interventions)

Table A2.2. Levels of Evidence (LE) rating scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table A2.3. Grades of Recommendation (GR) rating scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Methods used to formulate the recommendations — expert consensus.

Method of recommendation validation:

• External peer review

• Internal expert review

Description of the guideline validation method:

The draft of these recommendations was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations is easy to understand.

Comments were received from primary care pediatric oncologists regarding the clarity of the presentation of the recommendations and their assessment of the importance of the recommendations as a practical tool for daily practice.

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

Consultations and peer review: The draft recommendations were also reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final editing and quality control, the guidelines were re-analyzed by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account, and the risk of systematic bias in the development of the guidelines was minimized.

Clinical guideline updates: updating is carried out at least once every three years, taking into account new information on the diagnosis and management of patients with retinoblastoma. The decision to update is made by the Russian Ministry of Health based on proposals submitted by professional medical non-profit organizations. The formulated proposals must take into account the results of a comprehensive assessment of drugs and medical devices, as well as the results of clinical approbation.

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

Procedure for updating clinical guidelines.

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

Appendix A3. Reference Materials

A3.1. Classification of complications of varying severity resulting from the use of antineoplastic agents

Appendix B. Physician Action Algorithms

Figure 1. Flowchart for the diagnosis and management of a pediatric patient with retinoblastoma

Figure 2. Flowchart for the management of a patient with intraocular RB

Appendix C. Patient Information

1) Examinations in children should begin from birth (in the maternity hospital) and continue throughout childhood.

2) Preventive clinical examinations (dispensary monitoring) of the pediatric population with an ophthalmologist consultation are recommended every 3 months during the 1st year of life, including ophthalmoscopy with drug-induced mydriasis, and at least once every 6 months thereafter.

3) RB develops asymptomatically and covertly, manifests with leukocoria ("white pupil") or strabismus, and is life-threatening. Leukocoria ("white reflex", or "white pupil", instead of the normal "red reflex") is the most common indicative sign and is frequently noticed by the patient's parents.

4) In addition to ophthalmoscopy under anesthesia and drug-induced mydriasis, the main instrumental diagnostic methods for suspected RB include ocular ultrasound (ultrasonography), which helps detect a lesion with calcification characteristic of RB. Computed tomography can also detect calcification, but is not frequently used due to radiation exposure. The initial evaluation must include contrast-enhanced magnetic resonance imaging (MRI) of the orbits and brain to diagnose extraocular spread and rule out trilateral RB. Metastases without evidence of optic nerve tumor infiltration are rare. Cytological examination of cerebrospinal fluid and bone marrow aspirate, radioisotope bone scan, bone radiography with areas of pathological radiopharmaceutical uptake, punch biopsy of all accessible tumor sites followed by cytological examination, and testicular ultrasound in boys are indicated for patients with proven spread of RB beyond the globe.

5) In addition to the aforementioned methods, new auxiliary diagnostic modalities are emerging at the current stage. Optical coherence tomography may be recommended to confirm the diagnosis of RB, differentially diagnose other retinal conditions, determine minimal residual disease following eye-sparing treatment for intraocular RB, assess chorioretinal scar formation, or detect continued or occult tumor growth. To evaluate visual function after eye-sparing treatment, an electrophysiological study in an ophthalmology department, including electroretinography and visual evoked potentials, is recommended.

6) When RB is detected, molecular genetic testing is performed not only on the patient, but also on their family (siblings and parents).

7) At the present stage in Russia, the main treatment modalities for patients with RB are:

a) Eye-sparing treatment:

i) Local ophthalmological methods of RB treatment:

(1) Brachytherapy (BT) — suturing a radioactive plaque to the sclera of the eye in the projection of the RB, with a tumor thickness of no more than 6 mm;

(2) Transpupillary thermotherapy (TTT) — a type of laser treatment for intraocular RB with a thickness of no more than 3.0 mm; (3) Cryodestruction (freezing) is recommended when the thickness of the intraocular RB is no more than 4 mm;

ii) Systemic and local chemotherapy (intravitreal, selective intra-arterial), in case of contraindications to local ophthalmological treatment methods;

iii) External beam radiotherapy with an organ-preserving intent is currently not used;

b) Organ-ablation surgery when organ-preserving treatment has no prospect of success, as determined by the physician;

i) Enucleation — removal of the eye with a segment of the optic nerve.

8) High-dose chemotherapy with autologous HSCT when radical surgery is impossible, in disseminated RB, extraocular relapse, and trilateral RB.

9) External beam radiotherapy after eye enucleation for retrolaminar tumor invasion of the optic nerve, extra-scleral tumor spread and/or the presence of tumor cells at the resection margin of the optic nerve, as well as when it is impossible to perform radical surgery to remove the primary intraocular tumor, metastatic lesions of the central nervous system, lymph nodes, and distant metastasis sites, and for trilateral RB at the final stage of treatment.

10) Patients with any form of RB are not discharged from dispensary follow-up.

11) When planning a pregnancy, patients who have achieved remission are recommended to consult a geneticist (for carriers of germline mutations in the RB1 gene, prenatal and preimplantation diagnostics become available for family planning purposes).

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

No.