Extracranial Germ Cell Tumors: Clinical Guidelines

List of Abbreviations

ALT – alanine aminotransferase

AST – aspartate aminotransferase

AFP – alpha-fetoprotein

ESBL – extended-spectrum beta-lactamases

PEM – protein-energy malnutrition

β-hCG – beta-subunit of human chorionic gonadotropin

CBC – general clinical blood biochemistry

WHO – World Health Organization

GCT – germ cell tumor

DNA – deoxyribonucleic acid

IHC – immunohistochemical study

EIA – enzyme immunoassay

CT – computed tomography

LDH – lactate dehydrogenase

MRI – magnetic resonance imaging

MSCT – multislice computed tomography

MRSA – methicillin-resistant Staphylococcus aureus

MTS – metastatic lesions

YST – yolk sac tumor

PBSC – peripheral blood stem cell apheresis

PCT – polychemotherapy

PCR – polymerase chain reaction

PET – positron emission tomography

CRP – C-reactive protein

CINV – chemotherapy-induced nausea and vomiting

US – ultrasound examination

FN – febrile neutropenia

FSH – follicle-stimulating hormone

CC – choriocarcinoma

CE – cephalosporins

ECG – electrocardiogram

EchoCG – echocardiogram

EC – embryonal carcinoma

PEI – cisplatin, etoposide, ifosfamide

BEP – bleomycin, etoposide, cisplatin

GI – GIII – grade of malignancy of immature teratoma

SIOP – International Society of Paediatric Oncology

TNM – TNM Classification of Malignant Tumours

Terms and Definitions

Relapse-free survival (RFS) – the time from the achievement of remission to the date of relapse.

Overall survival (OS) – the time from the start of treatment to the end of the study or patient death.

Polychemotherapy – a regimen combining multiple chemotherapeutic agents, taking into account the dose, frequency, days, and route of administration.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Germ cell tumors (GCTs) originate from pluripotent primordial germ cells and represent a heterogeneous group of neoplasms with diverse histology, localization, clinical course, and prognosis [1]. Impairments in the differentiation of these cells lead to the development of embryonal carcinoma and teratoma (embryonic differentiation line) or choriocarcinoma and yolk sac tumor (extraembryonic differentiation pathway). Disruption in the development of unipotent primitive germ cells results in germinoma. GCTs can occur both gonadally and extragonadally. Extragonadal GCTs are located along the body's midline, i.e., along the migration pathway of primordial germ cells.

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

GCTs are neoplasms developing from primary germ cells of the human embryo, which normally form spermatozoa and ova [2]. Primary germ cells originate from the endoderm of the yolk sac and migrate along the hindgut to the urogenital ridge, where they become part of the developing gonads. If migration is impaired, germ cells may become arrested anywhere along their pathway and trigger tumor growth. Therefore, GCTs can arise both in the gonads and extragonadally, localizing along the midline. In children, GCTs are most commonly located in the testes (25%), ovaries (25%), sacrococcygeal region (20%), and brain (20%). Rare sites include the mediastinum (including the thymus), retroperitoneum, urogenital tract, nasopharynx, vagina, urinary bladder, and liver. The frequency of organ involvement varies by age. Neonates and infants under one year of age typically present with sacrococcygeal tumors, accounting for approximately 45% of all GCTs in this age group. In boys under 2 years of age, testicular involvement is more common. Gonadal GCTs are frequently associated with congenital malformations (cryptorchidism, gonadal dysgenesis, etc.).

GCTs metastasize via vascular channels to lymph nodes, lungs, or the liver.

Abnormal germ cell differentiation gives rise to various histological variants of GCTs. Disordered gonadal differentiation leads to germinomas, seminomas, and dysgerminomas. Impaired somatic differentiation results in teratomas of varying degrees of maturity and embryonal carcinomas, whereas extraembryonic differentiation leads to the development of yolk sac tumors and choriocarcinomas.

In addition to the so-called "pure variants" of GCTs, mixed tumors consisting of tissues of more than one histological type are distinguished. There are 3 grades of maturity for teratomas (T) depending on the content of immature embryonic tissue within the teratoma. The malignancy grade of these tumors varies.

1.3 Epidemiology of the Disease or Condition

GCTs account for less than 3% of all malignant neoplasms in children. Moreover, the biological features of germ cell tumors differ across various age groups [3].

GCTs are among rare types of tumors in children, accounting for 3–4% of all malignant neoplasms in children aged 0–15 years. Currently, there are no reliable epidemiological data on GCTs in children and adolescents in Russia. According to the German Children's Tumor Registry, teratomas account for 48.2% of cases, yolk sac tumors for 19.1%, mixed GCTs for 18%, germinomas for 12.2%, embryonal carcinomas for 1.6%, and choriocarcinomas for 0.9%. Among teratoma subtypes, mature teratoma is most frequently identified (54.5%), and malignant teratoma is less frequent (7.8%). Mature teratoma has the best prognosis.

Choriocarcinoma is the most aggressive histological type of GCT; therefore, untreated patients have the worst survival rates.

Extragonadal germ cell tumors are characteristic of infants in their first year of life, the majority of which are teratomas. Teratomas contain elements of all three germ layers (ectoderm, endoderm, and mesoderm). A mature teratoma consists of well-differentiated tissues. Immature teratoma is subdivided into three histological subtypes depending on the content of immature neuroglial or blastemal tissues. Teratomas (both mature and immature) may contain cells of various histological types of GCTs, and in rare cases, elements of other tumors (neuroblastomas, retinoblastomas). Teratomas are most frequently localized in the sacrococcygeal region.

Yolk sac tumors (YSTs) begin to predominate in infants in the second half of life. In the neonatal period, the incidence of GCTs is 2.6 per 100,000 in girls and 0.9 per 100,000 in boys. In adolescents (children older than 10 years), the incidence of GCTs is less than 0.1 per 100,000.

Testicular GCTs occur in infancy, and a second peak in the incidence of GCTs of this localization is observed in adolescents (7–8 per 100,000). In young males, testicular GCTs account for 14% of cases.

1.4 Features of Coding the Disease or Condition

• C38.1 – Malignant neoplasm of anterior mediastinum

• C48.0 – Malignant neoplasm of retroperitoneum

• C49.0 – Malignant neoplasm of connective and soft tissue of head, face and neck

• C49.5 – Malignant neoplasm of connective and soft tissue of pelvis

• C49.9 – Malignant neoplasm of connective and soft tissue of unspecified site

• C56 – Malignant neoplasm of ovary

• C62 – Malignant neoplasm of testis

  • C62.0 – Undescended testis

  • C62.1 – Descended testis

  • C62.9 – Testis, unspecified

• D15 – Benign neoplasm of other and unspecified thoracic organs

• D20 – Benign neoplasm of soft tissue of retroperitoneum and peritoneum

• D21 – Other benign neoplasms of connective and other soft tissue

• D28 – Benign neoplasm of other and unspecified female genital organs

• D29 – Benign neoplasm of male genital organs

• D36 – Benign neoplasm of other and unspecified sites

1.5 Classification of the disease or condition

1.5.1 WHO histological classification of germ cell tumors (Mostofi, Talerman) + modern grading system for teratomas*:

- teratoma (Table 1);

- germinoma (testicular seminoma, ovarian dysgerminoma);

- yolk sac tumor (YST);

- embryonal carcinoma (EC);

- choriocarcinoma (CC)

*Comment:

The grading system for teratomas is based on the number of microscopic fields (diameter – 4.5 mm, 40x magnification) containing aggregates of immature neuroepithelium in any section.

Table 1. Classification of teratoma maturity grade

Various histological variants can manifest both in a "pure" form and as mixed tumors.

Histological variants of teratoma with a malignant somatic component (+ carcinoma, neuroendocrine tumor, neuroblastoma, rhabdomyosarcoma, rhabdomyosarcoma + liposarcoma, chondrosarcoma, chondrosarcoma + primitive neuroectodermal tumor, malignant peripheral nerve sheath tumor) occur. Such teratomas generally have a worse prognosis.

1.5.2 Staging of GCTs

EXTRAGONADAL SITES: TNM (pretreatment, post-surgery)

T – primary tumor

TX – primary tumor cannot be assessed

T0 – no evidence of primary tumor

T1 – tumor limited to the organ

T1a – tumor ≤5 cm in diameter

T1b – tumor >5 cm in diameter

T2 – tumor invades adjacent organs

T2a – tumor ≤5 cm in diameter

T2b – tumor >5 cm in diameter

N – regional lymph nodes

NX – regional lymph nodes cannot be assessed

N0 – no regional lymph node metastasis

N1 – regional lymph node metastasis present

M – distant metastases

MX – distant metastases cannot be assessed

M0 – no distant metastasis

M1 – distant metastasis present

TESTICULAR TUMOR: LUGANO staging

LUGANO

I – Localized tumor

IA – tumor limited to the testis

IB – tumor infiltrates the spermatic cord or tumor in an undescended testis

IC – tumor infiltrates the scrotum, or prior surgery has been performed, or the tumor was excised or biopsied via a transscrotal approach

II – Spread of metastases to infradiaphragmatic lymph nodes

IIA – all nodes ≤2 cm

IIB – at least one node ranging from 2 to 5 cm in size

IIC – at least one node >5 cm in size

IID – palpable abdominal mass or fixed inguinal lymph nodes

III – Spread of metastases to supradiaphragmatic lymph nodes or distant metastases

IIIA – mediastinal and/or supraclavicular lymph nodes, with no distant hematogenous metastases

IIIB – distant metastases exclusively to the lungs:

"minimal": <5 metastases in each lung, all ≤2 cm in size

"advanced": >5 metastases in each lung or >2 cm pleural effusion

IIIC – hematogenous spread beyond the lungs

IIID – persistence of tumor markers following combination therapy, but without overtly detectable tumor

OVARIAN TUMOR: FIGO staging

FIGO

I – tumor confined to the ovaries or fallopian tubes

IA – tumor limited to one ovary (capsule intact), completely excised microscopically, no tumor cells in ascites or peritoneal washings

IB – bilateral tumor, confined to the ovaries, completely excised microscopically, capsule intact, no tumor cells in ascites or peritoneal washings

IC – tumor limited to one or both ovaries

- IC1 – intraoperative tumor rupture

- IC2 – rupture of the tumor capsule prior to surgery or tumor cells on the surface of the ovary or fallopian tube

- IC3 – tumor cells in ascites or peritoneal washings

II – involvement of one or both ovaries with extension into the pelvis or peritoneum

IIA – extension to the uterus and/or fallopian tubes

IIB – extension to other pelvic structures

III – involvement of one or both ovaries with microscopically confirmed peritoneal metastases outside the pelvis and/or retroperitoneal lymph node metastases

IIIА – histologically confirmed retroperitoneal lymph node metastases

IIIВ – peritoneal metastases (≤2 cm in diameter) outside the pelvis with or without retroperitoneal lymph node metastasis

IIIС – peritoneal metastases (>2 cm in diameter) outside the pelvis with or without retroperitoneal lymph node metastasis (including extension of the tumor to the liver or splenic capsule, without involvement of the parenchymal organs)

IV – distant metastases (excluding peritoneal carcinomatosis)

IVA – tumor cells in pleural effusion

IVB – parenchymal metastases to abdominal organs and extraabdominal organs (including inguinal and extraabdominal lymph nodes)

1.6 Clinical presentation of the disease or condition

Malignant GCTs can secrete tumor markers.

Elevated alpha-fetoprotein (AFP) levels are seen in patients with yolk sac tumors (YST), whereas elevated beta-human chorionic gonadotropin ($\beta$-hCG) levels are characteristic of choriocarcinoma (CC).

The levels of AFP and $\beta$-hCG correlate with the number of tumor cells producing them.

In healthy term newborns, serum AFP concentrations can vary widely, but normally the marker level decreases as the child grows (Table 26). Therefore, a progressive increase in AFP levels in infants may serve as a diagnostic criterion for a YST component, not requiring histological confirmation.

AFP and $\beta$-hCG markers are used for GCT diagnosis, assessing tumor response to therapy, and detecting recurrence.

Cytogenetic analysis (karyotyping) is indicated for GCTs to rule out disorders of sex development.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

1) anamnesis data;

2) physical examination findings;

3) laboratory test results;

4) instrumental examination data;

5) pathomorphological examination data of biopsy (surgical) material.

Clinical diagnosis is based on a combination of:

1) physical examination (visual inspection and palpation), revealing criteria pointing to a potential neoplasm of the testis, abdominal, or thoracic cavity.

2) laboratory tests, revealing elevated serum tumor markers (AFP, hCG);

3) morphological verification of the diagnosis (when tumor markers are within normal limits).

2.1 Complaints and Anamnesis

Comments: detailed collection of family history, detailed inquiry into the mother's obstetric history, characteristics of pregnancy and the patient's development from birth to the time of examination. Clarification of oncological history: presence of benign or malignant tumors in family members, as well as congenital malformations in the family or the patient.

Tumor localization in the soft tissues of the skull:

Impaired chewing, swallowing, and breathing.

Presence of a mass in the oral cavity (depending on tumor localization). Depending on the nature of spread: pain syndrome, including headache.

Tumor localization in the sacrococcygeal region:

Child's distress when attempting to sit.

Disorders of bowel and bladder function.

Appearance of a mass in the perianal and sacrococcygeal region.

Tumor localization in the testes:

Enlargement of the testis (painless or painful in early childhood, and more frequently painful in adolescents).

Quite often, a testicular mass in children under 7 years of age is detected during a routine medical check-up, followed by a scrotal ultrasound (during scheduled screening examinations by a pediatric surgeon and pediatric urologist-androloogist). Differential diagnosis must be performed with varicocele and testicular hematoma.

Tumor localization in the ovary/ovaries:

Abdominal pain, acute abdomen presentation.

Abdominal enlargement against the background of a relatively good general condition.

Appearance of vaginal discharge.

Pubertal development disorders.

Tumor localization in the retroperitoneal space:

Abdominal distension.

Abdominal pain.

Palpable abdominal mass.

Stool irregularities.

Dysuric disorders.

Tumor localization in the mediastinum:

Cough.

Dysphagia.

Cardiac arrhythmia.

The mass may be detected incidentally during routine X-ray examinations and/or thyroid ultrasound at scheduled intervals.

2.2 Physical Examination

Initial examination includes:

1) Complete physical examination

a. anthropometric measurements (weight, height, and body surface area)

b. nutritional status assessment (percentiles)

c. physical development assessment

d. evaluation for congenital malformations and dysmorphic stigmata

2) Assessment of the skin and mucous membranes

a. detection of café-au-lait spots

b. detection of a palpable mass, determination of localization, tumor characteristics (edema, tissue adhesion), degree of functional impairment

3) Assessment of the musculoskeletal system

a. detection of pain syndrome

b. detection of limb function impairment

4) Assessment of cardiovascular system function

5) Assessment of pulmonary system function

6) Abdominal palpation with assessment for hepatosplenomegaly

7) Assessment of lymph node size

a. involvement of regional lymph nodes; dimensions must be recorded in all cases.

8) Assessment of pelvic organ function

a. detection of internal organ dysfunction

2.3 Laboratory Diagnostics

Comments: markers are determined prior to treatment initiation (prior to surgery, including biopsy). When evaluating assay results, reference ranges of the specific laboratory must be used.

Tumor markers must be monitored dynamically at 5-7 day intervals.

An increase in tumor markers in typical locations (testes, ovaries) makes the clinical and radiological diagnosis of a secreting GCT unquestionable.

In cases of "secreting tumors", tumor marker assays should be repeated before each treatment phase

During chemotherapy, tumor markers should be monitored once every 7 days.

2.4 Instrumental Diagnostics

• It is recommended to perform the following instrumental diagnostic methods to assess disease stage, determine the patient's general condition, feasibility of surgical intervention and medical treatment, and the need for supportive and concomitant therapy [4] [5]:

  • Ultrasound of the primary tumor (tumor volume assessment) depending on localization: pelvic ultrasound (comprehensive), scrotal ultrasound, soft tissue ultrasound (one anatomical region).

• Computed tomography/Magnetic resonance imaging of the primary tumor depending on localization: contrast-enhanced chest CT; contrast-enhanced abdominal CT; contrast-enhanced pelvic CT in females; contrast-enhanced pelvic CT in males; contrast-enhanced MRI of the abdomen and retroperitoneum; contrast-enhanced pelvic MRI;

• Electrocardiography, echocardiography.

• Comprehensive ultrasound of the abdominal cavity and retroperitoneum, comprehensive pelvic ultrasound (transabdominal and transvaginal).

• Contrast-enhanced chest CT.

• Brain MRI with contrast in case of suspected stage 4 disease, in adolescents with primary tumor localization in the testis or mediastinum, and in patients with a histological diagnosis of choriocarcinoma.

• If necessary and/or in complex cases, PET-CT (positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals) may be considered.

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

2.5 Other Procedures

• For morphological verification of the diagnosis in patients with extragonadal primary tumor localization and normal specific tumor marker levels (AFP, beta-hCG), it is recommended to perform a biopsy of the primary tumor depending on localization: mediastinum, abdominal cavity, retroperitoneal space, sacrococcygeal region [6].

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

• In patients with verified germ cell tumor or suspected germ cell tumor, bone marrow puncture for cytological bone marrow examination is not recommended [7].

Comment: bone marrow involvement in germ cell tumors is extremely rare. Literature contains only isolated descriptions of bone marrow involvement in germ cell tumors.

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

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

Typical tumor localization and elevated serum concentrations of tumor markers allow a diagnosis of GCT to be established without morphological confirmation, which is particularly important in disseminated tumor processes.

The treatment strategy for GCTs is determined taking into account age, histological variant, tumor localization, disease stage, and tumor marker levels.

Surgical treatment

The first and most crucial therapeutic measure in extracranial GCTs is complete tumor resection.

Microscopically total tumor resection (R0) is one of the most significant prognostic factors.

In malignant GCTs, adjuvant chemotherapy is additionally required.

In unresectable tumors, neoadjuvant chemotherapy (CT) is primarily indicated to reduce tumor volume, achieve radical tumor removal, and prevent mutilating surgery.

Clinical diagnosis can possibly be established based on imaging methods and elevated tumor markers, which in isolated cases allows a biopsy to be omitted.

Combination chemotherapy comprising 3 drugs, one of which is always a platinum compound, has the highest efficacy.

Cisplatin** (P) is among the most effective drugs; however, it can lead to tubular renal dysfunction and hearing loss.

In comparison, #carboplatin** is less toxic. In patients with malignant GCTs in the first 4 months of life, a 2-drug combination of cisplatin** and etoposide** (intravenous administration) is used.

• At the initial stage, for a child with suspected GCT and normal tumor marker levels, it is recommended to perform surgical removal/biopsy of the primary tumor depending on localization: mediastinum/ovary/ovaries/testis/testesticles/sacrococcygeal region or other localizations, followed by pathomorphological examination (see section 7.2) [5].

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

Comments: under vital indications, biopsy/removal of the primary lesion (mediastinum/ovary/testis/sacrococcygeal region or other localizations) may be performed prior to the completion of the clinical workup. However, in standard situations, the extent of primary surgery should be considered only after completing a comprehensive evaluation. In the case of a clearly demarcated tumor with no evidence of infiltration into surrounding organs, radical surgery may be considered. Potential surgical risks should be minimized. In the case of tumor infiltration into vital structures as well as other organs and tissues, and in the presence of numerous postoperative complications, biopsy of the lesion is indicated, followed by decision-making on management tactics based on histological and IHC examination results.

Surgical Procedures in GCTs

Sacrococcygeal localization

Comment: Tumors localized in the sacrococcygeal region often present clinically as a huge mass. The dorsal approach is the most convenient. Infiltrated areas of the skin must be removed en bloc with the tumor, as subsequent closure of the operative field with skin is not problematic. Separation of the tumor from the rectum is possible under digital control. Bowel and bladder functions usually recover after surgery. Resection of the coccyx along with the tumor is absolutely mandatory for coccygeal localizations. The coccyx must be removed en bloc with the tumor to avoid tumor rupture.

In Altman type IV sacrococcygeal localization (a huge tumor component is located in the minor pelvis, including the coccygeal region), preoperative chemotherapy prior to surgery must be discussed in the case of a secreting GCT. In this case, an additional ventral approach is useful to achieve radical removal of the sacrococcygeal neoplasm en bloc. Thus, for sacrococcygeal localization, the tumor must be removed en bloc with the coccyx, which prevents recurrence in the majority of cases. For mature teratoma and in some cases of malignant GCT, radical surgery followed by meticulous follow-up observation is sufficient.

Ovarian tumors

Comment: In ovarian tumors, the abdominal midline approach provides a better intraoperative view than the traditional approach. In ovarian tumors, it is important to initially ligate the ovarian veins and arteries to prevent tumor cell dissemination. The adnexa of the infiltrated area must be removed en bloc with the tumor. For intraoperative staging, accurate tumor size, precise identification and cytology of intraperitoneal fluid, and examination of the contralateral area are important. It is necessary to biopsy all suspicious areas and distant lymph nodes (lymph node biopsy).

Patients with ovarian germinoma and a 46,XY karyotype should be discussed further regarding the removal of the contralateral ovary.

Testicular tumors

Other locations

Surgical access to other sites of primary localization, such as the mediastinum and retroperitoneal space, should be planned according to the clinical situation. Isolated retroperitoneal tumors are best treated similarly to coccygeal tumors. Most mediastinal tumors are typically located in the anterior mediastinum, causing clinical symptoms due to the displacement of adjacent structures. The surgical approach is predominantly a right-sided thoracotomy, and occasionally a sternotomy. In some cases, separating the tumor from large vessels or the hila of the lungs is problematic. Therefore, anatomical information obtained using imaging methods such as CT or MRI scanning is extremely important. If CT or MRI scanning reveals infiltration into surrounding tissue or metastases to lymph nodes, the liver, lungs, etc., the first therapeutic step will be primary chemotherapy after clinical diagnosis using tumor markers. In the case of infiltrative growth of a "non-secreting" tumor (i.e., AFP and β-hCG levels are not elevated), a tumor/soft tissue mass biopsy must be performed to confirm the histological diagnosis.

Biopsy

Tumor biopsy (mediastinal/ovarian/testicular/sacrococcygeal or other primary tumor locations) carries a risk of tumor cell dissemination. Therefore, a biopsy is indicated only in the case of a massive tumor with no possibility of complete resection, and when tumor markers are not elevated. In this case, the tumor type can only be diagnosed histologically. It is important to avoid complications during the biopsy. This means safe handling of the surrounding tissue, as well as defining the margins affected by the tumor.

Conservative treatment

Therapeutic options after surgical treatment (Table 2).

7.3.1. "PURE" TERATOMA AND TERATOMA WITH MICROFOCI: mature (G 0) and immature teratoma (G 1–2), malignant teratoma (G 3) (Gonzalez-Crussi grading system)

Table 2. Therapeutic options for patients with teratoma

Note. Ovarian teratoma with peritoneal gliomatosis – FIGO 1c – surgery only followed by monthly follow-up.

PATIENTS IN THE WATCHFUL WAITING GROUP

• Teratomas (Grade 0–2) of various localizations after radically performed surgery with regular!!! follow-up.

• Testicular malignant GCT stage IA after R0 in children under 2 years of age.

• Stage I ovarian tumors following radical surgery under regular follow-up (it is known that only 25% of patients in this group require further chemotherapy in the event of a relapse. Deferred chemotherapy does not lead to worsened survival in this group, while 75% will avoid chemotherapy-related toxicity) [12].

THERAPY OF EXTRAGONADAL MALIGNANT GCT [3]

Treatment regimens – see Appendix A3.1

Increasing the number of cycles in the absence of a response to therapy in the form of tumor reduction and/or normalization of tumor markers does not lead to a cure or relapse prevention.

These patients require alternative therapy outside of clinical guidelines.

Patients older than 10 years with malignant extragonadal GCT involving regional lymph nodes and distant metastases have the worst prognosis.

Following biopsy and 1 course of chemotherapy (for tumor containment), cases must be discussed with the Federal Center for the intensification of therapy outside of clinical guidelines.

7.3.4. THERAPY OF MALIGNANT TESTICULAR GERM CELL TUMORS [13]

Table 3. Therapeutic options for testicular GCT

- patients with tumor invasion into lymph nodes or blood vessels must be treated according to the high-risk group (with #ifosfamide**);

- in case of a delayed response to treatment (failure of tumor markers to normalize after 2 cycles of therapy) – discuss the patient with the Federal Center;

- unchanged tumor volume/rising tumor markers – "growing teratoma syndrome" – prompt surgery;

- unchanged tumor volume/rising tumor markers or delayed marker normalization/progression – change the risk group;

- patients with R1–2 tumor resection and/or "viable" tumor after 2nd look – intensification of therapy outside of clinical guidelines;

- adolescents with testicular teratoma are discussed for chemotherapy, as this group of patients has a high risk of distant delayed relapses (Table 3).

7.3.5. THERAPY OF MALIGNANT OVARIAN GERM CELL TUMORS [13]

Table 4. Therapeutic options for ovarian GCT

- in case of hepatoid or endometrioid differentiation of malignant ovarian germ cell tumors, therapy is administered according to a higher risk group (in stages III and IV – according to the high-risk therapy for extragonadal GCT);

- patients with FIGO stage I and tumor involvement in lymph nodes or blood vessels must be treated according to a higher risk group – FIGO stage II;

- in case of a delayed response (failure of tumor markers to normalize after 2 cycles of therapy) – discuss the patient with the Federal Center;

- unchanged tumor volume/rising tumor markers – "growing teratoma syndrome" – prompt surgery; unchanged tumor volume/rising tumor markers or delayed marker normalization/progression – change the risk group;

- Patients with R1–2 tumor resection and/or "viable" tumor after 2nd look – intensification of therapy outside of clinical guidelines (Table 4).

Comments: The optimal second-line regimen is chosen after consultation with the Federal Center!

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comments: the presence of a central venous catheter providing the ability to monitor CVP, frequent blood sampling, and a high rate of fluid administration is absolutely necessary at the initial stages of therapy and in high-risk patients receiving intensive high-dose chemotherapy.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: The scope, duration, and nature of rehabilitation measures depend on the patient's age at the time of initial diagnosis, the timing of rehabilitation measures, the scope of treatment received (polychemotherapy, surgery, radiation therapy, high-dose polychemotherapy and autologous hematopoietic stem cell transplantation, etc.), and comorbid conditions. The initiation of rehabilitation measures depends on the stage and risk group, begins during the initial polychemotherapy phases, and continues after its completion through all stages of follow-up. Rehabilitation measures are carried out under the supervision of a pediatric oncologist at the medical institution where the patient received all core stages of therapy. Rehabilitation is divided into medical, psychological, social, and other types. The program involves educators (preschool and school education), social workers, psychologists, and specialists in various fields (physical and rehabilitation medicine physicians, neurologists, pediatric endocrinologists, pediatric cardiologists, trauma surgeons, etc.). Rehabilitation is carried out in regional centers based on outpatient clinics and in specialized medical rehabilitation centers. The frequency of rehabilitation is 2–3 times a year and may be increased depending on the patient's psychosomatic status [25] [26] [27].

5. Prevention and Dispensary Observation

Table 5. Follow-up and dispensary monitoring

6. Organization of Medical Care

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

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

• presence of treatment-related complications (surgical intervention, radiation therapy, drug therapy, etc.) of GCT.

Indications for planned inpatient admission to a medical organization include:

• need for complex interventional diagnostic medical procedures requiring subsequent monitoring in an inpatient or day-care setting;

• presence of indications for specialized antitumor 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-care setting.

Indications for discharging a patient from a medical organization include:

• completion of a course of treatment or a stage of specialized, including high-tech, medical care in an inpatient or day-care setting, provided there are no treatment-related complications requiring drug correction and/or inpatient medical interventions;

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

• need to transfer the patient to another medical organization of the appropriate profile. The conclusion on the feasibility of transferring the patient to a specialized medical organization is made after a prior consultation based on the provided medical documents and/or preliminary examination data by specialist physicians of the target medical organization.

7. Additional Information

7.1 Determination of Resection Status in GCTs

Microscopically complete (R0):

• complete tumor resection en bloc with the organ of origin (in case of sacrococcygeal GCT — complete resection with the coccyx; in case of testicular GCT — entire testis via inguinal approach; in case of ovarian GCT — entire ovary with the fallopian tube);

• no prior biopsy;

• tumor cyst was not punctured and there was no rupture during surgery with spillage of contents;

• histological evaluation shows the tumor capsule or pseudocapsule is free of tumor cells (absence of tumor cells at the resection margin);

• absence of tumor cells in ascitic or peritoneal lavage fluid.

Macroscopically complete, microscopically residual (R1):

• removal of the entire tumor in multiple pieces, tumor removal during a re-operation;

• resection of the coccyx, ovary, or testis in separate pieces;

• transscrotal surgery for testicular tumors;

• violation of tumor capsule integrity, e.g., due to tumor rupture, tumor cyst puncture, or intraoperative biopsy for histological examination;

• tumor cells in ascitic or pleural effusion;

• tumor cells on the organ surface or at the resection margin.

Macroscopically residual (R2):

• enucleation of the tumor from the organ while preserving the organ: the entire coccyx, ovary, or testis;

• remnants of visible tumor or tissue infiltration;

• metastatic remnants within the surgical field, e.g., peritoneal implants (excluding gliomatosis) or metastatic involvement of regional lymph nodes. Distant metastases to the lungs, liver, or other sites are excluded;

• liquid consistency of the tumor.

Pseudocapsule formation occurs as a result of tumor compression by adjacent structures. Only a sufficient and safe margin guarantees the possibility of complete tumor resection.

If the tumor tissue is poorly demarcated, separate evaluation of sections beyond the suspicious area is mandatory for histological clarification, regardless of whether tumor invasion was noticed by the surgeon.

Removal and labeling of all lymph nodes for subsequent histological verification is required.

Definitions of complete or incomplete tumor resection.

Complete resection is defined as the removal of the entire volume of tumor tissue:

• for tumors localized in the coccygeal region, resection of the tumor, capsule, and coccyx en bloc is performed;

• for ovarian tumors, the ovary, ovarian appendage, and fallopian tube must be resected;

• for correct staging, regional lymph nodes are removed if necessary.

Incomplete resection is defined as resection where:

• capsule rupture occurred during or after surgery;

• tumor infiltration into surrounding tissues is detected or the tumor adheres (grows) to surrounding tissue, making complete tumor resection impossible. In case of tumor infiltration into surrounding tissue, histological examination of the tissue at the resection margins must be performed. The tumor pseudocapsule appears as a result of compression of adjacent structures by the tumor. Only a sufficient and safe margin guarantees the possibility of complete tumor resection.

If complete tumor resection is possible and stage 1a disease is precisely diagnosed, treatment may be completed at this stage in cases of ovarian or other extra-cranial localization, excluding sacrococcygeal localization. However, such patients must be closely monitored at strictly scheduled intervals.

7.2 Response Criteria

Complete response (CR)

• Absence of clinical signs of disease;

• Absence of tumor on contrast-enhanced imaging.

• Normal levels of tumor markers (AFP, β-hCG).

Partial response (PR)

• Reduction in the volume of the primary tumor and metastatic lesions by more than 50% (by maximum dimensions); if the sole manifestation of the disease was elevated tumor markers, a decrease of 90% or more.

• Absence of new tumor growth lesions.

• Normal levels of tumor markers (AFP, β-hCG).

Stable disease (SD)

• Reduction in the volume of the primary tumor and metastatic lesions by less than 50% of the sum of the volume of all measurable lesions.

• Absence of new tumor growth lesions.

• No dynamics and/or minor decrease in tumor markers (AFP or β-hCG).

Progressive disease (PD)

• Increase of more than 25% in the size of any measurable lesion.

• Appearance of new tumor growth lesions.

• Increase in tumor marker levels (excluding the first week of chemotherapy).

7.3 Therapeutic Options for Patients with Relapsed or Refractory GCTs

Drug therapy in the case of relapsed/refractory GCT involves curative and palliative treatment approaches. The optimal treatment regimen is determined by prior treatment history.

• Indicated with curative intent is tandem high-dose chemotherapy in the CarboPET regimen using #Carboplatin**+Etoposide**+Thiotepa with autologous peripheral stem cell support [13] (see Appendix A.3.1).

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

Comments: the decision on the feasibility and appropriateness of surgical resection and/or radiotherapy is made at a multidisciplinary medical meeting and following a consultation with the Federal Center!

7.3.1 Second-Line Therapy Regimens for Young Children

For young children (under 10 years of age) with refractory forms or relapses of GCT, the following chemotherapy regimens can be used: the JEB regimen, the high-dose CarboPET regimen [13] (see Appendix A3.1). The decision on choosing the optimal second-line therapy regimen is made individually for each patient after discussing the clinical situation with the Federal Center!

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Listed in alphabetical order

1. Dmitry G. Akhaladze, Doctor of Medical Sciences, Director of the Institute of Oncology and Pediatric Surgery, Deputy Chief Physician for Surgery

2. Svetlana R. Varfolomeeva, Doctor of Medical Sciences, Professor, President of RODOG, Director of the Research Institute of Pediatric Oncology and Hematology named after Acad. L.A. Durnov at the National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, Professor at the Department of Pediatric Oncology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

3. Nikolay V. Zhukov, Doctor of Medical Sciences, Head of the Department of Interdisciplinary Oncology Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.

4. Aleksandr I. Karachunskiy, Doctor of Medical Sciences, Director of the Institute of Oncology, Radiology, and Nuclear Medicine, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.

5. Denis Yu. Kachanov, Doctor of Medical Sciences, Deputy Director of the Institute of Oncology, Radiology, and Nuclear Medicine, Head of the Department of Clinical Oncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

6. Kirill I. Kirgizov, Candidate of Medical Sciences, Deputy Director for Research, Durnov Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

7. Dmitry V. Litvinov, Doctor of Medical Sciences, Chief Physician - Deputy General Director for Medical Work, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

8. Polina A. Naimushina, Pediatric Oncologist at the Department of Older Children Oncology and Hematology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

9. Liliya L. Rabaeva, Candidate of Medical Sciences, Head of the Department of Older Children Oncology and Hematology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

10. Marina V. Rubanskaya, Candidate of Medical Sciences, Head of Pediatric Oncology Department No. 1 (Chemotherapy of Thoracoabdominal Tumors), Durnov Research Institute of Pediatric Oncology and Hematology (NII DOiG), N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

11. Amina M. Suleimanova, Pediatric Oncologist, Senior Researcher at Pediatric Oncology Department No. 1 (Chemotherapy of Thoracoabdominal Tumors), Durnov Research Institute of Pediatric Oncology and Hematology (NII DOiG), N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

12. Denis V. Shevtsov, Pediatric Oncologist at the Department of Oncology, Pediatric Head and Neck Surgery, and Neurooncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

Conflict of interest: none declared

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Pediatric oncologists-hematologists.

2. Medical students, residents, postgraduate students

Table 6. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 7. Scale for assessing levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 8. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines.

The mechanism for updating 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 on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1. Chemotherapy Regimens with Supportive Care

Table 9. Cisplatin** / Etoposide** (PE) Regimen [13]

Table 10. Cisplatin**/etoposide**/#ifosfamide** (PEI) chemotherapy regimen [13]

Chemotherapy guidelines

• interval between chemotherapy cycles: 21 days;

• in children under 2 years of age or weighing less than 10 kg, the dose should be calculated per kg (30 kg = 1 m²);

• if the Karnofsky score is less than 50, the dose of #ifosfamide** is 1000 mg/m²/day, days 1–5;

• under the age of 4 months, #ifosfamide** is excluded from the treatment regimen;

• conditions for continuing chemotherapy:

  • white blood cell count greater than 1.5×10⁹/l and platelet count greater than 50×10⁹/l;

Second-Line Therapy Regimens

CarboPET chemotherapy regimen [13]

Table 11. Cycle 1 – #Carboplatin**+Etoposide**

Table 12. Cycle 2 – Thiotepa + Etoposide on day 28 from the start of cycle 1

TI-CE chemotherapy regimen [14] [86]

Table 13. Stage 1 – 2 cycles of induction chemotherapy with PBSC apheresis

Timing between cycles is 14 days

The target cell count for each reinfusion was at least 2×10 CD34 cells/kg of body weight.

Table 14. Stage 2 – 3 cycles of high-dose chemotherapy with autologous PBSC support

Timing between cycles is 21–28 days

TIP chemotherapy regimen [14] [31]

Table 15. TIP chemotherapy regimen

Timing between cycles is 21 days

#Gemcitabine**+#Paclitaxel** chemotherapy regimen [15]

Table 16. #Gemcitabine**+#Paclitaxel** chemotherapy regimen

Timing between cycles is 28 days

#Gemcitabine**+#Paclitaxel**+Oxaliplatin** chemotherapy regimen [32]

Table 17. #Gemcitabine**+ #Paclitaxel**+Oxaliplatin** chemotherapy regimen

Timing between cycles is 21 days

For young children (under 10 years of age) with refractory or relapsed GCO, the following chemotherapy regimens can be used: the JEB regimen, the high-dose CarboPET regimen [13]. The decision on choosing the optimal second-line therapy regimen is made individually for each patient after discussing the clinical situation with the Federal Center!

JEB chemotherapy regimen

Table 19. JEB chemotherapy regimen (#Carboplatin**+Etoposide**+Bleomycin**) [36]

Timing between cycles – 21 days

Appendix A3.2. Prevention and treatment of nausea and vomiting induced by antitumor therapy

A3.2.1 Determination of Emetogenic Risk Level and CINV Prevention Strategy

To select an adequate regimen for CINV prevention at the first stage, it is necessary to determine the emetogenic level (risk of CINV) of the antitumor therapy regimen planned for the patient. The emetogenic level affects the choice of drugs for CINV prevention, their doses, and duration of use [18].

Appendix A3.2.6 (Table 20) presents the general classification of emetogenicity of chemotherapy drugs according to ASCO (American Society of Clinical Oncology) guidelines [18] [37].

A3.2.2 Prevention of Nausea and Vomiting Associated with High-Emetogenicity Chemotherapy

For optimal prevention of acute CINV occurring on the day(s) of chemotherapy administration, for children aged 5 years and older and/or weighing 15 kg or more, it is appropriate to use a four-drug regimen including serotonin 5-HT3 receptor blockers, an NK1 receptor antagonist (other antiemetic drugs), #dexamethasone**, and #olanzapine** [18] [38] [39] [40]. Regimens and doses are presented in Appendix A3.2.7 (Table 21).

If the antitumor therapy regimen includes a glucocorticoid at a dose equal to or exceeding the dose indicated for antiemetic use, additional administration of a glucocorticoid (to the antitumor therapy regimen) for CINV prophylaxis on that day is not required. The use of #olanzapine** in children under 5 years of age and/or weighing less than 15 kg has not been studied and cannot be recommended.

For optimal prevention of delayed CINV administered within 3 days after completion of chemotherapy administration, it is appropriate to use a combination of #dexamethasone** and #olanzapine** [39] [41] [40]. Regimens and doses are presented in Appendix A3.2.7 (Table 21).

If it is not possible to prescribe an NK1 receptor antagonist (other antiemetic drugs), use a combination consisting of any serotonin 5-HT3 receptor blocker, #dexamethasone**, and #olanzapine** [41] [42] [40]. Regimens and doses are presented in Appendix A3.2.7 (Table 21).

If it is not possible to prescribe #dexamethasone**, palonosetron is used as the preferred serotonin 5-HT3 receptor blocker in combination with an NK1 receptor antagonist (other antiemetic drugs, if prescription is possible) and #olanzapine** [43] [44]. Regimens and doses are presented in Appendix A3.2.7 (Table 21).

A3.2.3 Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Chemotherapy

For optimal prevention of acute CINV occurring on the day(s) of chemotherapy administration, use a two-drug regimen including a serotonin 5-HT3 receptor blocker and #dexamethasone** [18]. Regimens and doses are presented in Appendix A3.2.7 (Table 21).

If the antitumor therapy regimen includes a glucocorticoid at a dose equal to or exceeding the dose indicated for antiemetic use, additional administration of a glucocorticoid (to the antitumor therapy regimen) for CINV prophylaxis on that day is not required.

For optimal prevention of delayed CINV administered within 1 day after completion of antitumor drug administration, use #dexamethasone** [18]. Regimens and doses are presented in Appendix A3.2.6 (Table 1).

If it is not possible to prescribe #dexamethasone**, use a combination consisting of any serotonin 5-HT3 receptor blocker and an NK1 receptor antagonist (other antiemetic drugs). Regimens and doses are presented in Appendix A3.2.7 (Table 21).

If it is not possible to prescribe both #dexamethasone** and NK1 receptor antagonists (other antiemetic drugs), use palonosetron as the preferred serotonin 5-HT3 receptor blocker [18] [45]. Regimens and doses are presented in Appendix A3.2.7 (Table 21).

A3.2.4 Prevention of Nausea and Vomiting Associated with Low- and Minimal-Emetogenicity Chemotherapy

Prevention of CINV during low- and minimal-emetogenic chemotherapy involves single-agent prophylaxis with serotonin 5-HT3 receptor antagonists for low-emetogenic therapy, or no prophylaxis at all in the case of chemotherapy with minimal emetogenic potential [18]. Regimens and doses are presented in Appendix A3.2.7 (Table 21).

A3.2.5 Treatment of Breakthrough and Refractory Emesis

Patients with breakthrough and refractory vomiting during cytostatic therapy are indicated for:

1. If breakthrough CINV occurs during cytostatic therapy (and consequently prophylaxis) classified as minimal, low, or moderate emetic risk, it is necessary to use the agents specified for the next higher level of prophylaxis.

2. If the patient is already receiving prophylaxis intended for highly emetogenic therapy, then in the event of breakthrough CINV, the addition of #olanzapine** should be considered (if it was not used previously due to inappropriate age or body weight). If #olanzapine** cannot be used, metoclopramide** may be used as an alternative.

If the patient experiences refractory CINV and is not yet receiving the maximum level of prophylaxis, escalation of antiemetic therapy is required. If refractory CINV occurs despite the maximum level of prophylaxis, switching the current serotonin 5-HT3 receptor antagonist to palonosetron or administering additional doses of serotonin 5-HT3 receptor antagonists is possible. If these prophylactic approaches fail, the continuous addition of #olanzapine**, metoclopramide**, or other drugs that have proven effective in treating breakthrough vomiting in the patient is indicated [46].

A3.2.6 Table 20 – Emetogenic Risk Levels of Antineoplastic Agents

A3.2.7 Table 21 – Doses and Regimens of Antiemetic Drugs

Appendix A3.3. Guidelines for Nutritional Status Assessment and Correction

A3.3.1 Nutritional Screening and Monitoring

All patients upon hospital admission and subsequently 1 to 4 times a month are indicated to undergo nutritional screening (screening assessment of nutritional status) to detect protein-energy malnutrition or the risk of its development [47] [28] [48]

Identification of nutritional disorders in the early stages of their development, especially before the start of antineoplastic therapy, allows for timely initiation of nutritional correction. Criteria for protein-energy malnutrition, obesity, and nutritional risk factors – see Appendix A3.3.2. Initial screening is performed either by assessing anthropometric parameters and identifying risk, or by using standard scales/instruments for nutritional screening [49].

Nutritional screening consists of the initial and subsequent regular assessment of nutritional status and the risk of developing protein-energy malnutrition, including occult malnutrition, in every patient from the moment of hospital admission. The frequency should be determined by the specific clinical situation and the characteristics of the ongoing treatment [29].

To conduct nutritional screening, it is necessary to use special validated questionnaires/instruments; their use is particularly relevant at the stage of initial admission to the hospital and/or at the (subsequent) stage of admission to the clinical department [29] [50].

Most screening tools are focused on combining data on the primary diagnosis, clinical status, anthropometric parameters, changes in body weight, nutritional status, and integrating these data into a total score with subsequent division of patients into 2 or 3 cohorts: do not require nutritional correction (support); require re-screening over time ("at-risk" group); require nutritional correction (support). The clinical unit (or institution) has the right to use the tool, or combination of tools, that it considers most appropriate for conducting nutritional screening among its patients. It must be remembered that existing screening tools are not designed to answer the question about the volume and method of necessary nutritional support, and do not carry prognostic information for a specific patient, since their application is aimed exclusively at medical triage. In addition, there is no universal screening tool in pediatrics

For the initial (general) assessment of nutritional status and identification of nutritional risk, it is necessary to take into account anthropometric parameters, changes in body weight over a certain period (3, 6, or 12 months), nutritional data (regimen, habitual dietary composition, specific features of food intake, possible eating disorders, presence of food intolerance/allergies), endocrine status data (data on identified endocrine disorders in the child), and data on identified gastrointestinal disorders [29] [50].

As an obligatory minimum of basic anthropometric parameters for the initial and regular assessment of nutritional status, the following must be used: body weight, height (body length), body mass index [29] [47].

As additional anthropometric parameters in case of need for a detailed anthropometric study for the initial and regular assessment of nutritional status, the following are used: measurement of circumferences, lengths, skinfold thickness, handgrip dynamometry [28] [47].

To correlate the obtained anthropometric data (height, body weight, body mass index, arm circumference) with normative values for the pediatric population, reference values (scales) are used, either from local (national) references or global commonly used nomograms: centile values/percentiles, or the magnitude of deviation of the obtained value from the population mean (SDS or z-score) [47] [50].

Commonly used "by default" in the Russian Federation are WHO growth charts, for the convenience of working with which there are freely available programs (WHO anthro and WHO anthro plus) that quickly allow calculating key anthropometric parameters in correlation with WHO reference data. However, it is possible to use other reference data to correlate patient data with standards – in this case, it is necessary to indicate which specific references were used.

Patients with identified nutritional disorders upon initial screening are recommended a more detailed examination of nutritional status: dietary analysis, assessment of body tissue composition, assessment of laboratory parameters, as well as a detailed physical examination and interview to identify nutritional and metabolic disorders and their predictors [29].

Due to the high prevalence of body composition disorders and tissue imbalance in the form of occult protein-energy malnutrition (sarcopenia), occult obesity (accumulation of fat mass) in the pediatric oncology population, as well as the prevalence of edema (including occult edema) and disorders of fluid compartment distribution, assessment of body composition by various available methods is indicated: bioelectrical impedance analysis, dual-energy X-ray absorptiometry, MRI, CT, etc. – for clarifying and in-depth assessment of body composition in risk groups. These groups are as follows: chronic protein-energy malnutrition, prolonged (more than 2 months) need for parenteral nutrition, inclusion of hormonal drugs in therapy, CNS tumors, chronic eating disorders (feeding disorders), HSCT recipients with identified anthropometric nutritional disorders [29] [50].

All patients receiving nutritional support are indicated to undergo nutritional monitoring, which includes an interview, anthropometry, analysis of tissue body composition, and laboratory parameters (general clinical biochemical blood test, coprological examination) [29] [51]

A3.3.2 Nutritional Support

All patients with protein-energy malnutrition or a high risk of its development (regardless of nutritional status) are indicated to receive nutritional support (NS) [29].

The presence of protein-energy malnutrition or a high risk of its development in children with malignancies during antitumor treatment leads to associated risks of increased disability, increased duration and scope of primary and supportive treatment, low success rate of the ongoing treatment, increased mortality, and overall financial costs for treatment and rehabilitation measures—during active antitumor treatment and after its completion. Occult protein-energy malnutrition (e.g., due to excess fat mass during long-term glucocorticoid therapy) is accompanied by the same risks. Therefore, given the high likelihood of exacerbating nutritional problems during treatment, it is advisable to prescribe nutritional support to patients in addition to their existing diet or as a replacement for it.

Patients with obesity (excess fat mass) may develop occult protein-energy malnutrition, defined by a deficit of fat-free body mass and a critical decrease in its skeletal muscle compartment; therefore, correction of this type of deficiency is indicated. The presence of obesity in itself is not a contraindication for enteral or parenteral nutritional support [50] [52] [53].

When choosing the form, method, type, and volume of nutritional support, one must be guided primarily by the principle of an individual patient-centered approach—in accordance with the clinical situation and logic [29].

If the patient cannot/will not/is not ready to independently consume the prescribed volume of the formula in the required regimen, the placement of a nasogastric or nasointestinal tube or gastrostomy is indicated [29] [54].

Lack of appetite, unwillingness to eat and take enteral nutrition formulas, swallowing disorders, and the inability to meet nutrient and energy requirements orally are indications for enteral nutrition via a nasogastric feeding tube. The presence of pathological conditions in which the patient must not take food naturally (acute pancreatitis, gastric outlet stenosis, high proximal fistulas) indicates the implementation of enteral nutrition via a sterile single-use nasojejunal tube.

If there is a current or potential need for tube feeding lasting more than 6 weeks, gastrostomy is indicated [29].

When the need for long-term enteral nutrition is identified and the risk of nutritional deficiency is predicted (including during chemoradiotherapy), preventive gastrostomy may be performed, bypassing the tube-feeding stage.

The key indication for prescribing parenteral nutrition (PN) is the inability to meet the patient's estimated nutritional requirements (at least at the level of basal energy expenditure) via the enteral route – whether current or potentially anticipated in the short term.

Parenteral nutrition should be initiated gradually, stepwise increasing the volume (and rate) of the daily infusion, starting from one-third to half of the calculated target volume and, under the monitoring of general therapeutic biochemical blood test parameters (primarily glucose, direct bilirubin, urea), acid-base balance and blood gas analysis studies, reaching the target volume over several days (the rate of reaching the target volume is determined individually based on the clinical situation). Discontinuation of parenteral nutrition should also be performed gradually, stepwise, in reverse order.

It is highly undesirable to prescribe parenteral nutrition immediately at full volume, just as it is to discontinue full parenteral nutrition at once ("starting the next day"). It is especially dangerous to prescribe full parenteral nutrition to patients with a prolonged lack of nutrition due to the potential development of refeeding syndrome. The volume of parenteral nutrition should be increased gradually (stepwise) under parallel monitoring of acid-base balance and blood gases, electrolytes, glucose, urea, and direct bilirubin in the blood. If necessary, the volume and composition of parenteral nutrition should be adjusted.

A3.3.3. Reference and information tables for assessing nutritional status and its correction.

Table 22. Interpretation of nutritional status based on Z-score according to WHO reference data [48].

Notes: nutritional status in pediatric oncology is assessed using cumulative data (clinical, laboratory, instrumental), taking into account nutritional risk; anthropometric indicators allow for a criteria-based orientation in determining nutritional status and cannot be the sole determining factors [50].

* – the indicator with the minimum SDS is used in determining nutritional status; SDS – standard deviation score; obesity – simple; hypothalamic; in neuroendocrine diseases; iatrogenic; monogenic; syndromic

Table 23. High-risk factors for the development of nutritional status disorders [50]

Table 24. Main screening tools for identifying the risk of nutritional disorders in pediatrics [51] [50]

Table 25. Recommended nutritional and energy requirements for children (per kg of body weight per day) when calculating diet therapy and enteral nutrition [55].

Notes: Requirements are provided as a guideline for calculating and prescribing enteral nutrition; they do not cancel or replace a patient-centered approach in prescribing nutritional support: in each specific case, the clinical picture, possible metabolic and organ dysfunctions should be taken into account, and nutrient intake should be adjusted considering the child's capability and tolerance

Appendix A3.4. Blood Transfusion Support

Order of the Russian Ministry of Health No. 1170n dated October 28, 2020, "On Approval of the Rules for Providing Medical Care to the Population in the Profile 'Transfusiology'", registered with the Russian Ministry of Justice on 27.11.2020 No. 61123, regulates the procedure for blood transfusion support for patients in need of this type of medical care.

Children with malignant neoplasms receiving chemotherapy and/or radiation therapy, presenting with severe anemia (Hb ˂70 g/L, Ht ˂25%) with symptoms and signs of anemic hypoxia and without bleeding, are recommended to receive transfusions of red blood cell components of donor blood [56].

Transfusions may not be required for well-compensated patients recovering from induced aplasia. However, in the case of upcoming intensive chemotherapy in the absence of clinical manifestations of anemic syndrome, transfusions of donor red blood cell components may be justified. The decision to use transfusions should be based primarily on clinical rather than laboratory data [57] [58].

Stable pediatric patients with malignant neoplasms in the absence of bleeding are indicated to receive transfusions of red blood cell components of donor blood at a dose of 10-15 ml per kg of body weight [57] [58].

Pediatric patients with oncological diseases undergo transfusions of leukoreduced donor blood components [59].

It has been shown that the use of leukoreduced donor blood components reduces the incidence of febrile non-hemolytic transfusion reactions and also significantly reduces the likelihood of patient HLA-alloimmunization and the transmission of certain transfusion-transmitted infections (cytomegalovirus, Epstein-Barr virus).

To prevent transfusion-associated graft-versus-host disease, patients with malignant diseases receiving chemotherapy and/or radiation therapy and experiencing immunosuppression are recommended to receive transfusions of cellular blood components irradiated with ionizing radiation at a dose of 25 Gy [59].

In children with malignant neoplasms and hypoproliferative thrombocytopenia caused by the underlying disease and/or its treatment, prophylactic platelet concentrate transfusions are indicated under the following conditions [60]:

• stable neonates with a platelet count drop to ≤25×10⁹/L;

• stable patients with a platelet count drop to ≤10×10⁹/L;

• febrile patients with a platelet count drop to ≤15×10⁹/L;

• patients at high risk of bleeding with a platelet count drop to ≤20×10⁹/L;

• prior to minor surgical procedures in non-critical sites with a platelet count drop to ≤20×10⁹/L;

• prior to lumbar puncture, with a platelet count drop to ≤40×10⁹/L;

• prior to percutaneous liver biopsy, if the platelet count is ≤50×10⁹/L;

• during surgical interventions in critical locations (e.g., central nervous system), if the platelet count is ≤75-100×10⁹/L;

• prior to other surgical interventions with a platelet count of ≤50×10⁹/L

Patients receiving antithrombotic agents, patients with disseminated intravascular coagulation, sepsis, etc., have an increased risk of bleeding.

Platelet concentrate transfusions in children with hypoproliferative thrombocytopenia and hemorrhagic syndrome are used in [60]:

• minor hemorrhagic syndrome and a platelet count drop to ≤10×10⁹/L;

• moderate hemorrhagic syndrome and a platelet count drop to ≤20×10⁹/L;

• severe hemorrhagic syndrome and a platelet count drop to ≤30×10⁹/L;

• bleeding in a critically important location (e.g., CNS) and a platelet count drop to ≤100×10⁹/L

Platelet transfusions in children with malignant neoplasms are indicated at the following dose [60]:

• neonates 10-15 mL/kg

• children with a body weight of more than 10 kg: 10 mL/kg

Granulocyte concentrate transfusions are indicated for children with oncological diseases and severe, prolonged neutropenia (neutrophil count less than 200/mcL) in the presence of a severe bacterial or fungal infection unresponsive to adequate antimicrobial therapy [59].

Transfusions of donor fresh frozen blood plasma are indicated for children with oncological diseases in the presence of clinically significant bleeding combined with an increase in activated partial thromboplastin time (APTT) and/or international normalized ratio (INR) of more than 1.5 times the upper limit of normal [59].

Transfusions of donor fresh frozen plasma to children with malignant neoplasms are indicated at a dose of 15 ml/kg of body weight [59].

Cryoprecipitate transfusions in children with oncological diseases are indicated when the fibrinogen concentration drops below 1-1.5 g/L [61].

Cryoprecipitate transfusions for acquired fibrinogen deficiency caused by various reasons are indicated when its serum concentration drops below 1 g/L. Cryoprecipitate transfusions when its blood concentration drops below 1.5 g/L are indicated for patients with acute promyelocytic leukemia, severe intraoperative bleeding, and patients with sepsis who develop hemorrhagic syndrome.

Appendix A3.5. Specifics of venous access in ensuring successful diagnostic and therapeutic interventions in children with oncological and hematological diseases.

3.5.1 General specifics of venous access.

The manufacturer's instructions and documentation supplied with the venous access device provide key information about the device, potential flow rates and pressure limits during infusion, and priming volume to all personnel involved in daily patient care or diagnostic procedures [62]. This documentation must be readily and continuously available to the personnel working with the patient.

3.5.2 Device Selection Recommendations

The choice of venous access device should be based on the patient's needs and take into account:

• Diagnosis, management plan, and expected duration of intravenous treatment;

• Patient age;

• Possible patient preferences regarding the type or location of the device;

• The condition of the patient's veins;

• Available resources for device installation and maintenance.

There is insufficient evidence to establish the clear superiority of one device over another for every patient category. It is advisable to use a central venous catheter with the smallest number of lumens [63].

If there are contraindications to inserting a central venous catheter through the superior vena cava basin veins, central venous catheters inserted via the femoral vein are used.

For continuous use (daily or at least once a week), external catheters such as PICC and CICC are indicated; for intermittent use (less than once a week), totally implantable systems (port) (implantable infusion/injection port/catheter***) are indicated [62].

3.5.3 Device Placement Recommendations

Central venous access devices are inserted according to urgent and elective indications in an aseptic operating room. A detailed description is available in the FAR clinical guidelines.

The choice of vein depends on the condition of the patient's venous system. It is preferable to use devices that allow high flow rates and contrast media administration [64] [65]. Efforts should be made to ensure that the ratio of the central venous catheter diameter to the vein diameter does not exceed 1/3.

The use of multi-lumen central venous catheters, although indicated for certain specific patient categories, is associated with an increased risk of infection [66] [67].

The material of the central venous catheter must be chosen based on high flow characteristics and pressure resistance, as well as device durability.

3.5.4. Venous access care and removal.

Venous access care is performed in compliance with asepsis and antisepsis rules; periodic dressing changes, flushing of the venous access, its "locking" in case of intermittent treatment, and removal according to indications are indicated [68].

Appendix A3.6. Prevention and Treatment of Infections

3.6.1 Standard Definitions Used

Neutropenia is defined as a granulocyte count of less than 0.5×10⁹/L, or less than 1.0×10⁹/L with an anticipated decline over the next few days.

Fever – a single body temperature elevation ≥ 38.3°C or a body temperature ≥ 37.8°C persisting for one hour or more.

Hypothermia is a decrease in body temperature below 36°C. This indicator is an important sign of an infectious process, especially in young children and patients receiving glucocorticoids.

Fever of unknown origin – a condition characterized by fever in the absence of clinical and radiological manifestations of infection and microbiological data.

Bacteremia is the identification of a microorganism from a blood culture taken during a febrile episode that is not a contaminant. False bacteremia includes the identification of so-called contaminating microorganisms—skin commensals of the hands: coagulase-negative staphylococci, Propionibacterium spp., Micrococcus spp., etc.—when identified only once.

Proven infection is defined as one in which a microorganism is identified from sterile body sites (blood, cerebrospinal fluid, urine, biopsy material) in the presence of symptoms of an inflammatory response, or the isolation of a pathogen from non-sterile sites (skin, mucous membranes, gastrointestinal tract) with a corresponding local clinical presentation of infection.

Probable infection is defined as one in which no microorganism is identified from the studied media, but there are clinical and/or radiological signs of infection with a rapid response to anti-infective therapy.

Febrile neutropenia is a symptom complex combining the development of fever or hypothermia in a patient with criteria for neutropenia. It is the most anticipated infectious complication and develops in the vast majority of high-risk patients, and less frequently in standard-risk patients.

Patients with hematological malignancies belong to the standard risk group. In this group, the expected duration of neutropenia is less than 7 days.

3.6.2 Antibacterial Therapy

When febrile neutropenia develops, after drawing blood for microbiological blood culture for sterility, the immediate intravenous administration of broad-spectrum antibiotics (systemic antibacterial drugs) is indicated—for stable patients, the maximum allowable interval should not exceed 60 minutes, and in case of hemodynamic instability, 30 minutes [24] [69] [70]. All other necessary diagnostic workups must be performed after initiating the starting therapy.

When febrile neutropenia develops, it is necessary to initiate empirical broad-spectrum antibiotic therapy with activity against gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa. The choice of starting therapy depends on the risk group, the patient's somatic status, local epidemiological data and guidelines, as well as screening results and the patient's prior infection history [70] [21]. For patients in the standard risk group, the administration of third-generation cephalosporins (CP) is indicated [21].

Appropriate options for empirical antibiotic therapy:

• #Piperacillin+[Tazobactam] 300 (400) mg/kg/day in 3–4 doses or by continuous infusion (maximum daily dose 16 g) +/- #amikacin** 15–22.5 mg/kg/day in a single dose) [71]

• #Cefepime** (150 mg/kg/day in 3 doses (maximum daily dose 6 g) +/- #amikacin** 15–22.5 mg/kg/day in a single dose) [71].

• #Cefoperazone+[Sulbactam]** 40–80 mg/kg/day (4 g twice daily or 160 mg/kg/day calculated by cefoperazone in 3 doses +/- #amikacin** 15–22.5 mg/kg/day in a single dose) [71].

• Ceftazidime** (2 g 3 times daily or 100–150 mg/kg/day in 3 doses) [71].

1. In clinics with a low detection rate of ESBL-producing Enterobacteriaceae, the following may be prescribed:

• #Cefepime** (2 g 3 times daily or 100–150 mg/kg/day in 3 doses) [71].

• Ceftazidime** (2 g 3 times daily, intravenously or 100–150 mg/kg/day in 3 doses) [71].

The administration of intravenous vancomycin** in addition to the baseline drug in first-line therapy is indicated for the development of ulcerative necrotic stomatitis, soft tissue lesions, suspected catheter-related infection (prior to microbiological confirmation), in patients after chemotherapy using high doses of cytarabine**, and in cases of the patient's prior colonization with methicillin-resistant Staphylococcus aureus (MRSA);

2. For severe infection, carbapenems may be prescribed in first-line therapy (intra-abdominal infection, soft tissue lesions of the perirectal region, etc.):

• #Imipenem+[Cilastatin]** 60–100 mg/kg/day in 3–4 doses + #amikacin** 15–20 mg/kg/day in a single dose) [71].

• #Meropenem** 60 mg/kg/day every 8 hours; for severe infection, 120 mg/kg/day every 8 hours (maximum daily dose 6 g) + #amikacin** 15–20 mg/kg/day in a single dose) [71].

3. If anaerobic infection is suspected (gingivitis, perioral cellulitis, intra-abdominal or perirectal infection), it is necessary to prescribe antibiotics with anti-anaerobic activity (#Piperacillin+[Tazobactam], #Imipenem+[Cilastatin]**, #metronidazole*) [71, 72].

4. For clostridial infection or diarrhea when C. difficile toxin in stool cannot be determined—#metronidazole** (0.5 g every 8 hours intravenously or 10 mg/kg every 8 hours). In severe enterocolitis, oral administration of vancomycin** at a total daily dose of 500 mg 4 times a day is possible [72].

5. In case of allergy to beta-lactam antibacterial drugs, penicillins, fluoroquinolones may be prescribed as an alternative regimen:

• #Levofloxacin** (10 mg/kg twice daily IV for children under 5 years, 10 mg/kg IV in a single dose (maximum 750 mg/day) for children over 5 years [73].

Modification of antimicrobial therapy is based on clinical symptoms, instrumental, and microbiological studies. If fever persists while patients are in a stable clinical condition, it is acceptable to await a clinical response to initial antibacterial therapy within 48–72 hours, as fever is not the sole indicator of the severity of the infectious process. In patients with persistent febrile neutropenia and negative blood culture, modification takes into account the susceptibility of Gram-negative bacteria colonizing the intestinal mucosa. Reserve-line drugs include #colistimethate sodium, polymyxin B**, #tigecycline**, #ceftolozane+[tazobactam]**, ceftazidime+[avibactam]** (in certain situations in combination with aztreonam).

Recommended doses:

• #Colistimethate sodium – loading dose 118,000 IU/kg, then 74,000 IU/kg every 12 hours (maximum 320 mg × 2 times/day) [74]

• Polymyxin B** 2.5 mg/kg/day divided into 2 doses; in children under 1 year of age, 4 mg/kg/day divided into 2 doses

• #Tigecycline**

#Tigecycline** (children aged 2.5 to 8 years): loading dose 2 mg/kg (100 mg), then 1.2 mg/kg (50 mg) every 12 hours [75].

#Tigecycline** (children aged 8 to 11 years and 12 to 17 years): 1.2 mg/kg every 12 hours (maximum dose 50 mg), then 50 mg every 12 hours [75].

• #Ceftazidime+[avibactam]** 120 mg/kg/day IV based on ceftazidime every 8 hours for children aged 3–5 months, 150 mg/kg/day IV every 8 hours for children over 6 months of age (maximum daily dose 6 g) [76].

• If #ceftazidime+[avibactam]** needs to be prescribed in combination with aztreonam**, the drugs must be administered simultaneously via parallel infusions.

If signs of sepsis and septic shock develop, systemic antibacterial drugs with the broadest possible spectrum of action should be prescribed: carbapenems combined with aminoglycosides and vancomycin**, and in patients with known colonization, reserve-line drugs. If severe infectious complications and/or sepsis develop, systemic antibacterial drugs are prescribed at maximum doses, preferably as prolonged infusions due to impaired clearance and fluid redistribution in the body [77] [78] [79].

When infections associated with Gram-positive flora develop, the choice of systemic antibacterial drugs should be guided by susceptibility data and maximum efficacy in the specific clinical context:

3.6.4 Empirical Systemic Antifungal Therapy

If fever persists for 96–120 hours despite ongoing first- and second-line empirical antibacterial therapy, and there are no foci of infection, initiate empirical antifungal therapy [80] [81] [82]:

• Caspofungin** (children older than 3 months) 70 mg/m² on the first day (not exceeding 70 mg per day), then 50 mg/m² (not exceeding 70 mg per day) intravenously once daily

• Amphotericin B [liposomal] (children older than 1 month) (3 mg/kg/day as a single infusion)

• Alternative drugs include other echinocandins (other systemic antifungal agents) – micafungin** [81]:

- Micafungin** (children older than 16 years): body weight >40 kg – 100 mg/day, body weight <40 kg: 2 mg/kg/day;

- Micafungin** (children older than 4 months and younger than 16 years): body weight >40 kg – 100 mg/day, body weight <40 kg: 2 mg/kg/day;

- Micafungin** (children <4 months): 4–10 mg/kg/day.

Appendix A3.7. Alpha-Fetoprotein Levels in Healthy Newborns

Table 26. Alpha-fetoprotein levels in healthy newborns

Appendix B. Physician Action Algorithms

Algorithm 1. For children with newly diagnosed gonadal tumors.

Algorithm 2. For children with newly diagnosed extragonadal tumors along the midline of the body

Appendix C. Patient Information

Germ cell tumors are a relatively rare disease in children, with a population frequency of 4–6 cases per 1 million children. Germ cell tumors develop from primordial germ cell precursors (embryonic somatic cells). Depending on the specific location, this group of diseases includes: gonadal germ cell tumors (testes and ovaries), as well as extragonadal locations (sacrococcygeal region, anterior mediastinum, retroperitoneal tissue, vagina, kidney). Tumors in the stomach, neck, and orbit are extremely rare.

Treatment approaches for these diseases differ somewhat: for gonadal locations, surgical treatment is indicated as the first step; for extragonadal locations, treatment begins with chemotherapy.

Two peak ages for the incidence of germ cell tumors in children have been established: under 3 years of age (sacrococcygeal, testicular, vaginal, orbital, neck, and retroperitoneal locations) and after 12 years of age (ovarian, testicular, and mediastinal).

The primary danger of ovarian germ cell tumors is tumor rupture, which can cause dissemination of the process across the peritoneum. In testicular germ cell tumors, metastasis to regional and retroperitoneal lymph nodes can lead to compression of major veins and thrombosis. Germ cell tumors located in the sacrococcygeal region can cause intestinal obstruction (i.e., completely blocking the intestinal lumen and preventing the passage of food), cause constipation, and impair urination. All germ cell tumors can metastasize (i.e., form new foci of disease) in regional and distant lymph nodes, as well as in other organs (most commonly the lungs, and more rarely the liver, brain, and bones). Metastatic brain involvement leads to neurological symptoms. Fortunately, today the vast majority of even advanced forms of germ cell tumors are successfully cured, provided that treatment is initially managed by a qualified specialist in this field.

Most patients can make a full recovery and return to a full, normal lifestyle. Exceptions include situations where germ cell tumors are located in the mediastinum, as well as following extended biopsy for GCTs in non-specialized facilities, a prolonged diagnostic phase, and the detection of multiple metastases in the liver and brain. However, even in such cases, when a complete cure is not possible, patients' life expectancy can be significantly increased and symptoms alleviated.

The treatment of germ cell tumors in children is not a task for a single specialist. Depending on the specific situation, the clinic must have a qualified surgeon, pediatric oncologist, anesthesiologist-resuscitologist, cardiologist, and neurologist.

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

Appendix G1. Karnofsky Performance Scale [83].

Name in Russian: Karnofsky Scale.

Original title: Karnofsky Performance Status.

Source (official developer website, validation publication):

Karnofsky D.A., Burchenal J.H. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C. (ed.). Evaluation of chemotherapeutic agents. New York: Columbia University Press; 1949:191–205 [83].

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 and interpretation:

Notes: assessment of the patient's general condition is performed for all patients with GCT at the initial visit, as well as at each subsequent visit (examination, consultation) with a pediatric oncologist (B01.009.001, B01.009.002), before each subsequent course of chemotherapy, when evaluating response to therapy during treatment, and during follow-up.

Appendix G2. ECOG Performance Status Scale [84].

Original title: The ECOG Scale of Performance Status

Source: Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am. J. Clin. Oncol. 1982;5(6):649–65 [84].

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Content and interpretation:

Notes: assessment of the patient's general condition is performed for all patients with GCT at the initial visit, as well as at each subsequent visit (examination, consultation) with a pediatric oncologist (B01.009.001, B01.009.002), before each subsequent course of chemotherapy, when evaluating response to therapy during treatment, and during follow-up.