Germ cell tumors in men: clinical guidelines

List of Abbreviations

AFP – alpha-fetoprotein

WHO – World Health Organization

CT – computed tomography

LDH – lactate dehydrogenase

PT – physical therapy

ICD-10 – International Statistical Classification of Diseases and Related Health Problems 10th Revision

MRI – magnetic resonance imaging

OR – orchifuniculectomy

PET-CT – positron emission tomography combined with computed tomography

RF – Russian Federation

RP – radiopharmaceutical

US – ultrasound examination

hCG – human chorionic gonadotropin (free β-subunit)

AJCC – American Joint Committee on Cancer

IGCCCG – International Germ Cell Cancer Collaborative Group

UICC – Union for International Cancer Control

TNM – (stands for tumor, node, and metastasis) international classification of cancer stages

Terms and Definitions

Retroperitoneal lymph node dissection – surgical removal of retroperitoneal lymph nodes (Retroperitoneal lymphadenectomy, Video-assisted retroperitoneal lymphadenectomy, Extended retroperitoneal lymphadenectomy, Robot-assisted extended retroperitoneal lymphadenectomy, Removal of retroperitoneal neoplasm, Laparoscopic removal of abdominal and retroperitoneal neoplasms).

Orchifuniculectomy – surgical removal of the testis affected by the primary tumor.

Prerehabilitation – rehabilitation from the moment of diagnosis until the start of surgical treatment / chemotherapy / radiation therapy.

First stage of rehabilitation – rehabilitation during the period of specialized treatment for the primary disease (including surgical treatment / chemotherapy / radiation therapy) in departments of medical organizations specialized in the primary disease.

Second stage of rehabilitation – rehabilitation in inpatient settings of medical organizations (rehabilitation centers, rehabilitation departments) during the early recovery period of the disease, late rehabilitation period, and the period of residual effects of the disease.

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

Lung resection – all types of surgical interventions for metastatic lung lesions (Lobectomy [removal of a lung lobe], Lobectomy. Simultaneous bilateral lung surgery, Extended lobectomy for lung neoplasms, Extended bilobectomy for lung neoplasms, Removal of lung neoplasm [atypical resection], Simultaneous bilateral lung surgery, Robot-assisted removal of lung neoplasm [atypical resection], Video-assisted thoracoscopic removal of lung neoplasm [atypical resection], Pneumonectomy, Pneumonectomy with resection and reconstruction of the tracheal bifurcation, Combined pneumonectomy, Extended pneumonectomy, Pneumonectomy. Video-assisted thoracoscopic lung resection, Video-assisted thoracoscopic pneumonectomy, Lung resection [more than one lobe], Video-assisted thoracoscopic lung resection, Anatomic segmentectomy of the lung, Segmentectomy of the lung. Simultaneous bilateral lung surgery, Video-assisted thoracoscopic lung segmentectomy, Sublobar atypical lung resection, Reconstructive and plastic interventions on the chest wall and diaphragm for lung tumors)

Liver resection – all types of surgical treatment for liver neoplasms (Removal of a liver lobe, Laparoscopic wedge [atypical] liver resection, Robot-assisted anatomic liver resection, Robot-assisted median liver resection, Resection of liver segment[s] using video-endoscopic technologies, Resection of liver segment[s] with a reconstructive-plastic component, Resection of liver segment[s] combined with angioplasty, Resection of liver segment S1, Resection of liver segments S7, S8, Left-sided caval lobectomy of the liver [S2 + S3], Resection of two liver segments [bisegmentectomy], Resection of three liver segments [S5 + S6 + S4 or S5 + S6 + S7], Laparoscopic bisegmentectomy of the liver, hemihepatectomy, Radiofrequency ablation, thermoablation, cryodestruction of liver tumors).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Germ cell tumors – a group of malignant tumors originating from germ cells.

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

The etiology of germ cell tumors remains unclear. There is evidence of an increased risk of tumors associated with exogenous hyperestrogenism (prenatal due to gestosis, or from dietary phytoestrogens) [1]. Factors associated with the development of germ cell tumors include cryptorchidism (5–10-fold increased risk), infertility (10–20-fold increased risk), testicular dysgenesis syndrome, and the presence of a germ cell tumor in a 1st-degree relative (5–10-fold increased risk) [2-4].

According to the most widespread theory, testicular germ cell tumors originate from primordial germ cells (PGCs)/gonocytes that have undergone differentiation arrest [5,6]. Cells with blocked or delayed differentiation prematurely enter meiosis, leading to polyploidization and the accumulation of genetic instability. During malignant transformation, PGCs and gonocytes form pre-invasive lesions of germ cell tumor in situ, which subsequently progress to an invasive tumor and acquire metastatic potential. Germ cell tumors in situ are always found at the periphery of invasive germ cell tumors and in 5% of cases in the contralateral testis.

1.3 Epidemiology of the Disease or Condition

Germ cell tumors are rare: in European countries and Russia, they account for about 1.3% of all cancer cases in men. However, in patients aged 20–25 years, they are (along with lymphomas) the most frequent malignant neoplasms. In approximately 90% of cases, germ cell tumors are localized in the testis (accounting for up to 95% of all malignant testicular tumors), and less frequently in the retroperitoneum, anterior mediastinum, or brain. Epidemiological data on extragonadal germ cell tumors in the Russian Federation (RF) are lacking. In 2018, 1,480 new cases of testicular tumors were registered in Russia, and 330 (22%) patients died from this cause in 2018, which is several times higher than the mortality rate in Western European countries (4%) [7].

1.4 Features of Coding the Disease or Condition

According to the International Statistical Classification of Diseases and Related Health Problems 10th Revision (hereinafter referred to as ICD-10), germ cell tumors are classified according to the primary site of origin: for example, a posterior mediastinal germ cell tumor is coded as C38.2, and a germ cell tumor of an undescended testis as C62.0.

Malignant neoplasm of heart, mediastinum and pleura (C38)

C38.1 Anterior mediastinum

C38.2 Posterior mediastinum

C38.3 Mediastinum, unspecified part

C38.8 Lesion of heart, mediastinum and pleura overlapping one or more of the above subcategories

Malignant neoplasm of retroperitoneum and peritoneum (C48)

C48.0 Malignant neoplasm of retroperitoneum

C48.8 Malignant neoplasm of retroperitoneum and peritoneum overlapping one or more of the above subcategories

Malignant neoplasm of testis (C62)

C62.0 Malignant neoplasm of undescended testis

C62.1 Malignant neoplasm of descended testis

C62.9 Malignant neoplasm of testis, unspecified

Neoplasm of uncertain or unknown behavior of male genital organs (D40)

D40.1 Neoplasm of uncertain or unknown behavior of testis

1.5 Classification of the disease or condition

International Histological Classification

International Histological Classification of Testicular Germ Cell Tumors (World Health Organization [WHO] Classification, 2016) [8].

Germ cell tumors derived from germ cell neoplasia in situ

Non-invasive germ cell tumors

9064/2 Germ cell neoplasia in situ

9064/2 Specific forms of intratubular germ cell neoplasia

Tumors of one histologic type (pure forms)

9061/3 Seminoma

9061/3 Seminoma with syncytiotrophoblastic cells

Non-seminomatous germ cell tumors

9070/3 Embryonal carcinoma

9071/3 Yolk sac tumor, postpubertal type

Trophoblastic tumors

9100/3 Choriocarcinoma

Non-choriocarcinomatous trophoblastic tumors

9104/3 Placental site trophoblastic tumor

9105/3 Epithelioid trophoblastic tumor

Cystic trophoblastic tumor

9080/3 Teratoma, postpubertal type

9084/3 Teratoma with somatic-type malignant component

Non-seminomatous germ cell tumors of more than one histologic type

9080/3 Mixed germ cell tumor

Germ cell tumors of unknown type

9080/1 Regressed germ cell tumor

Germ cell tumors unrelated to germ cell neoplasia in situ

9063/3 Spermatocytic tumor

9084/0 Teratoma, prepubertal type

Dermoid cyst

Epidermoid cyst

8240/3 Well-differentiated neuroendocrine tumor (monodermal teratoma)

9085/3 Mixed teratoma and yolk sac tumor, prepubertal type

9071/3 Yolk sac tumor, prepubertal type

Staging

Staging of testicular tumors is carried out in accordance with the TNM AJCC/UICC (American Joint Committee on Cancer & Union for International Cancer Control) 8th edition classification (2017) (Table 1) [9], while extragonadal retroperitoneal and mediastinal tumors, as well as patients with IS, II, and III stages of testicular tumors, are staged according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification (Table 2) [10].

Testicular tumor staging according to the TNM AJCC/UICC 8th edition classification (2017)

T – Primary tumor

Except for pTis and pT4, where radical orchiectomy (RO) is not strictly necessary for classification, the extent of the primary tumor is determined after RO.

pT category

pT_X – primary tumor cannot be assessed (category pT_X applies when RO is not performed).

pT0 – no evidence of primary tumor (e.g., histologically verified scar in the testis).

pTis – germ cell neoplasia in situ.

pT1 – tumor is limited to the testis and epididymis without vascular/lymphatic invasion; tumor may invade the tunica albuginea but not the tunica vaginalis.

pT2 – tumor is limited to the testis and epididymis, with vascular/lymphatic invasion, or tumor extends through the tunica albuginea and involves the tunica vaginalis.

pT3 – tumor invades the spermatic cord, with or without vascular/lymphatic invasion.

pT4 – tumor invades the scrotum, with or without vascular/lymphatic invasion.

N – Regional lymph nodes

Regional lymph nodes include retroperitoneal and iliac lymph nodes. Inguinal lymph nodes are considered distant for testicular tumors and are rarely involved. However, if a patient's normal lymphatic drainage pathways have been disrupted by previous surgical procedures in the inguinal region (orchidopexy, herniotomy, etc.), metastases in the inguinal lymph nodes in this case are classified as regional.

Clinical assessment

N_X – regional lymph nodes cannot be assessed.

N0 – no regional lymph node metastases.

N1 – metastases in one or more lymph nodes <2 cm in greatest dimension.

N2 – metastases in one or more lymph nodes <5 cm in greatest dimension.

N3 – metastases in lymph nodes >5 cm in greatest dimension.

Pathomorphological assessment

pNX – regional lymph nodes cannot be assessed.

pN0 – no regional lymph node metastases.

pN1 – metastases <2 cm in greatest dimension involving up to 5 nodes.

pN2 – metastases <5 cm in greatest dimension involving up to 5 nodes, or tumor extension beyond the lymph node capsule.

pN3 – metastases in one or more lymph nodes >5 cm in greatest dimension.

M – Distant metastasis

M_X – distant metastasis cannot be assessed.

M0 – no distant metastasis.

M1 – distant metastasis is present.

M1a – non-regional lymph node(s) or lung metastases.

M1b – other distant metastases are present.

S – serum tumor markers

S_X – serum marker levels cannot be assessed.

S0 – marker levels are within normal limits.

S1 – lactate dehydrogenase (LDH) level <1.5 N, human chorionic gonadotropin (hCG) <5,000 mIU/mL, alpha-fetoprotein (AFP) <1,000 IU/mL.

S2 – LDH 1.5–10 N, or hCG 5,000–50,000 mIU/mL, or AFP 1,000–10,000 IU/mL.

S3 – LDH >10 N, or hCG >50,000 mIU/mL, or AFP >10,000 IU/mL.

Table 1. Stage grouping according to the TNM8 classification (2017)

International Germ Cell Cancer Collaborative Group Classification

Table 2. IGCCCG classification (for TNM stage IS, II, and III tumors, primary retroperitoneal and mediastinal tumors) [10]

Note. AFP – alpha-fetoprotein; ULN – upper limit of normal; LDH – lactate dehydrogenase; hCG – human chorionic gonadotropin.

* To convert AFP levels from IU/mL to ng/mL, multiply the value in IU/mL by a correction factor of 1.21 (e.g., 1000 IU/mL = 1210 ng/mL).

** An LDH level >2.5 × ULN in seminomatous tumors is associated with decreased patient survival and likely requires more intensive therapy (as for intermediate prognosis).

1.6 Clinical presentation of the disease or condition

Testicular cancer presents as a painless, less frequently mildly painful, cartilage-like mass with irregular edges. Rarely, the disease manifests acutely, which may be due to testicular torsion or acute orchitis. The most frequent site of metastasis is regional retroperitoneal lymph nodes. Among distant metastases, involvement of the lungs, intrathoracic, and supraclavicular lymph nodes is most common; non-seminomatous tumors may also present with non-pulmonary visceral metastases (in the liver and brain). Metastases in retroperitoneal lymph nodes usually manifest as lower back pain, or abdominal pain when large in size. Elevated hCG levels can result in bilateral gynecomastia and the clinical picture of hyperthyroidism. Metastatic involvement of the lungs and mediastinal lymph nodes may manifest as dyspnea, hemoptysis, or superior vena cava syndrome.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition (see appendices B1, B2, B12):

1) history data;

2) physical examination findings;

3) laboratory test results;

4) instrumental diagnostic findings;

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

The clinical diagnosis is based on a combination of:

1) physical examination (visual inspection and palpation) revealing criteria indicative of a potential testicular neoplasm;

2) laboratory tests revealing elevated serum tumor markers (AFP, human chorionic gonadotropin (free beta-subunit) serum level);

3) morphological verification of the diagnosis.

In patients with a typical clinical presentation and high tumor marker levels (AFP and hCG) accompanied by clinically significant symptoms due to tumor dissemination, chemotherapy may be initiated even in the absence of morphological verification.

2.1 Complaints and Anamnesis

2.2 Physical Examination

Physical examination findings characteristic of patients with germ cell tumors are described in subsection 1.6.

2.3 Laboratory Diagnostics

• In patients with germ cell tumors and suspected germ cell tumors, it is recommended to perform a complete blood count (CBC) with differential, a general clinical blood chemistry panel, serum LDH activity, serum hCG level, and serum AFP level to identify factors that may influence the choice of treatment strategy, diagnostic methods, and secondary prevention [12,13].

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

Comments: prior to each chemotherapy cycle, a complete blood count (CBC) with differential, a general clinical blood chemistry panel, and tumor marker assessments (serum AFP and hCG, as well as blood LDH activity if previously elevated) are required. Other laboratory tests are performed as clinically indicated.

• In patients with germ cell tumors and suspected germ cell tumors, it is recommended to perform a pathomorphological examination of biopsy (surgical) material, including the following characteristics in the pathology report to determine the disease stage, select therapy, and assess prognosis:

1) histological structure of the tumor in accordance with the current WHO classification, indicating the proportion of each tumor component;

2) tumor dimensions;

3) pT stage (presence of lymphovascular invasion, involvement of the rete testis, testicular tunics, spermatic cord);

4) pN stage (total number of examined and metastatic lymph nodes, size of metastatic deposits, presence of extranodal extension);

5) presence of the spermatic cord resection margin involvement (a negative result must also be stated);

6) presence of therapeutic pathomorphosis according to the TRG scale (if chemotherapy was previously administered) [14].

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

Comments: a small testicular tumor must be sampled entirely, while for tumors up to 10 cm in the greatest dimension, 1 block per each 1 cm of the tumor should be taken; for large tumors, at least 10 blocks. It is necessary to sample the testicular tissue at the border with the tumor and away from the tumor, the testis and the tumor with the tunica albuginea, since vascular and lymphatic invasion is best evaluated in the peritumoral zone or beneath the tunica albuginea.

AFP levels cannot be elevated in seminoma. If the AFP level is elevated >20 ng/ml, treatment must be carried out as for non-seminomatous tumors, regardless of the pathological examination result of the biopsy (surgical) specimen. A high plasma hCG level (≥1000 mIU/ml) may also indicate the presence of a non-seminomatous tumor component.

2.4 Instrumental Diagnostics

Comments: CT of the abdominal cavity, retroperitoneal space, and chest cavity is the standard for staging and diagnostic workup in germ cell tumors of the testis, retroperitoneum, and mediastinum in most developed countries.

Comment: if it is impossible to perform contrast-enhanced brain MRI (waiting list time > 1 month), intravenous contrast-enhanced brain CT is acceptable. Brain CT without intravenous contrast is not recommended.

Comment: bone metastases in germ cell tumors are a relatively rare phenomenon. Therefore, whole-body bone scintigraphy is performed only when CT or MRI reveals findings suspicious for bone metastatic changes.

2.5 Other Procedures

• In case of doubtful ultrasound and/or MRI findings of the scrotum regarding the origin of a focal testicular lesion and with normal AFP and hCG levels, it is recommended to perform a testicular biopsy [11].

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

Comments: options for testicular biopsy are intraoperative excisional (preferred) or percutaneous core biopsy. Theoretically, the latter may promote tumor dissemination within the scrotum, although convincing evidence confirming this is lacking.

Comments: biopsy of the healthy contralateral testis may be performed, especially in case of its atrophy (volume <12 ml) at a young age (under 30 years) or a history of cryptorchidism. In this case, the risk of germ cell tumor in situ reaches 33% [20].

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

The prescription and use of medicinal products indicated in the clinical guidelines are aimed at providing the patient with clinically effective and safe medical care; therefore, their prescription and use in a specific clinical situation are determined in accordance with the instructions for use of specific medicinal products, implementing the precautions presented in the instructions, and dose adjustments are also possible taking into account the patient's condition.

3.1. Medical therapy

• In patients with germ cell tumors, it is recommended to administer antitumor drug therapy in accordance with the general principles outlined in the "Practical Guidelines for General Aspects of Antitumor Drug Therapy" of the Russian Society of Clinical Oncology [93]. In patients with germ cell tumors, chemotherapy is used, including cisplatin**, etoposide**, bleomycin**, carboplatin**, ifosfamide**, ^#paclitaxel**, #gemcitabine**, #oxaliplatin**, vinblastine** [11,13,21-27]. The principles of drug selection, their combinations, and the number of cycles depending on the stage are presented in section 3.4.

GUR CLOE 5Grading of Recommendations Assessment, Development, and Evaluation (GRADE) – C (Level of Evidence – 5).

• Before starting chemotherapy, it is recommended to discuss with the patient the need for cryopreservation of gametes (oocytes, spermatozoa) to preserve reproductive function [11].

GUR CLOE 5Grading of Recommendations Assessment, Development, and Evaluation (GRADE) – C (Level of Evidence – 5).

Comments: The cryopreservation procedure must be performed before chemotherapy.

3.2. Surgical treatment

Surgical treatment for germ cell tumors, depending on the clinical situation, may include orchiectomy, testicular resection, retroperitoneal lymph node dissection, mediastinal tumor resection, lung resection, and liver resection. Indications for each procedure depending on the disease stage are presented in section 3.4.

3.3. Radiation therapy

Radiation therapy (external beam radiotherapy, stereotactic body radiation therapy) is rarely recommended for the treatment of germ cell tumors. Indications for use, irradiation fields, and doses depending on the disease stage are presented in section 3.4.

3.4. Choice of treatment method depending on the stage of the disease

See treatment algorithms in Appendices B3–B11, B13.

3.4.1. Treatment of stage 0 disease (germ cell neoplasia in situ)

• If testicular germ cell tumor in situ is detected without an invasive tumor component (e.g., as an incidental finding on a biopsy for infertility), a biopsy of the contralateral testis is recommended to detect germ cell tumor in situ [28].

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

• If germ cell tumor in situ is present in one testis while the second testis is healthy, performing an orchiectomy is recommended to eradicate the tumor, or close surveillance (if the patient refuses orchiectomy) [28].

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

Comments: performing a double testicular biopsy increases the chance of detecting germ cell tumor in situ. In the absence of treatment for 5 years, germ cell tumor in situ progresses to invasive germ cell tumor in 50% of cases. If germ cell tumor in situ is detected, treatment may be delayed until the partner achieves pregnancy, provided there is close surveillance.

• If germ cell tumor in situ is present in both testes or affects a solitary testis, external beam radiation therapy to the male genital organs targeting the affected testis is recommended to eradicate the tumor (fraction dose 2 Gy, total dose 20 Gy) [29,30].

GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4).

3.4.2. Treatment of Stage I Disease (pT1–T4N0M0), Normalization of Marker Levels after Orchiectomy

• For clinically localized stage I testicular germ cell tumors, orchiectomy is recommended as radical therapy at the first stage of treatment. Organ-sparing treatment (testicular excision) is possible under strict indications [11,30].

GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4).

Comments: testicular resection is not indicated in the presence of a second healthy testis, but may be considered as an alternative to orchiectomy in patients with synchronous bilateral tumors, metachronous tumor of the contralateral testis, or a tumor in a solitary testis with a normal preoperative testosterone level and a tumor size <30% of the organ volume. Given the high (at least 82%) incidence of concomitant germ cell tumor in situ, testicular resection requires mandatory adjuvant external beam radiation therapy to the male genital organs targeting the testis at a dose of 16-20 Gy with a 2 Gy fractionation to prevent recurrence. In a man planning to father children, radiation therapy may be postponed until the woman achieves pregnancy, provided there is regular ultrasound monitoring of the contralateral healthy testis. Radiation therapy leads to complete infertility and Leydig cell dysfunction, although partially hormone-producing function may be preserved, which reduces the need for testosterone replacement therapy [29].

• In patients with stage I testicular tumor and initially elevated AFP or hCG levels after orchiectomy, monitoring of their dynamics is recommended every 7–10 days until normalization or stabilization/increase [11,12,31].

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

Comments: The adequate half-life of AFP is less than 5–7 days, and of hCG is less than 3 days. Indications for adjuvant chemotherapy are determined by recurrence risk factors and the patient's ability and desire to undergo intensive surveillance in case of refusing chemotherapy. The most important risk factor in stage I non-seminomatous tumors is the presence of lymphovascular invasion. In patients with vascular invasion, the risk of recurrence is about 50%, whereas in patients without invasion, it is about 20% [20].

• If AFP and hCG levels fail to normalize or stabilize in patients with T1–T4N0M0 testicular tumor stage, stage IS is diagnosed, and chemotherapy following the principles developed for the treatment of stages II–III is recommended to prevent tumor growth and metastasis [11,12,31].

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

• In the absence of lymphovascular invasion, surveillance is recommended for patients with non-seminomatous testicular tumors to prevent tumor recurrence [11,12,31].

GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4).

• For patients with non-seminomatous tumors with tumor invasion into the testicular vessels, administering 1 cycle of chemotherapy with the BEP combination (see Appendix A3) is recommended to prevent tumor metastasis within up to 6 weeks after primary tumor removal [11,12,32].

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

Comments: 1 cycle of BEP achieves a 97% 5-year disease-free survival and 99% overall survival. For those patients who refuse surveillance or adjuvant chemotherapy, prophylactic nerve-sparing retroperitoneal lymph node dissection can be offered

• For the majority of patients with stage T1–T4N0M0 seminoma, active surveillance is recommended, which should be carried out for at least 5 years for early diagnosis of tumor recurrence [32].

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

Comments: In seminoma, risk factors include primary tumor size ≥5 cm, rete testis invasion (RTI), and lymphovascular invasion (LVI). Depending on the combination of these factors, the risk of recurrence varies from 8% to 44%.

• If active surveillance is impossible or refused, upon patient preference, or in case of high recurrence risk, adjuvant therapy is recommended using one of the equally effective options:

– external beam radiation therapy for retroperitoneal neoplasms targeting para-aortic lymph nodes (total focal dose [TFD] 20 Gy), or

– adjuvant chemotherapy with carboplatin** (1 cycle at AUC 7) [101].

Level of Evidence BGrade of Evidence 3Level of recommendation validity – B (level of data reliability – 3).

Comments: When administering radiation therapy, it is crucial to ensure adequate shielding of the healthy testis. If the patient has previously undergone surgery in the inguinal region or scrotum, the radiation field is extended to the ipsilateral inguino-iliac regions with a TFD of 20 Gy, 10 fractions over 2 weeks (so-called dog-leg RT). Radiation therapy is associated with an increased risk of secondary malignancies.

3.4.3. Treatment of Advanced Stages of the Disease (Stages II–III of Germ Cell Tumors of the Testis, All Primary Extragonadal Malignant Germ Cell Tumors)

• In patients with testicular tumor involvement, radical inguinal orchiectomy is recommended at the first stage for diagnostic and therapeutic purposes [11].

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

• In patients with malignant extragonadal germ cell tumors of the retroperitoneum or mediastinum, chemotherapy is recommended as the first-line treatment (for regimens, see Appendix A3) in accordance with the IGCCCG prognostic classification to improve treatment outcomes and patient survival [11,31].

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

• In patients with mature teratoma and normal levels of AFP, hCG, and LDH, radical surgical treatment without prior chemotherapy is recommended to improve treatment outcomes and patient survival [11,31].

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

Comments: If a patient who has not previously received chemotherapy is found to have a malignant germ cell tumor in the resected specimen, postoperative chemotherapy according to the BEP regimen is recommended (2 cycles following R0 resection and 4 cycles following R1–2 resection).

• In patients with stage IIA/B seminoma (retroperitoneal lymph node metastases ≤5 cm), treatment using one of the options is recommended (see diagram in Appendix B3):

1) systemic chemotherapy similar to stage IIC patients [11,21,24,31];

GPR CLOE 5Grade of Recommendation – C (Level of Evidence – 5);

2) external beam radiation therapy for retroperitoneal neoplasms targeting the para-aortic and ipsilateral iliac regions (Dogleg) up to a total dose of 30 Gy (for stage IIA) and 36 Gy (for stage IIB) [16,94];

GPR BLOE 3Grade of Recommendation – B (Level of Evidence – 3);

3) nerve-sparing retroperitoneal lymphadenectomy [95,96]

GPR CLOE 4Grade of Recommendation – C (Level of Evidence – 4);

• In patients with stage IIA/B non-seminomatous germ cell tumors (retroperitoneal lymph node metastases ≤5 cm), it is recommended to administer treatment according to one of the options (see the scheme in Appendix B8):

1) systemic chemotherapy similar to stage IIC patients [11, 21, 24, 31];

GPR ALOE 2Grade of Recommendation – A (Level of Evidence – 2);

2) nerve-sparing retroperitoneal lymphadenectomy followed by active surveillance or 2 cycles of the EP regimen [97];

GPR CLOE 3Grade of Recommendation – C (Level of Evidence – 3);

• In patients with advanced disease stages and favorable prognosis, it is recommended to administer 3 cycles of chemotherapy with the BEP combination or 4 cycles of treatment with the EP combination (for regimens, see Appendix A3) to prevent tumor growth and metastasis [11,21,24,31].

GPR ALOE 2Grade of Recommendation – A (Level of Evidence – 2).

Comments: in patients with stage II-III seminoma, an elevated LDH level above 2.5 × ULN is an unfavorable prognostic sign. In such situations, to reduce the risk of progression, chemotherapy dose intensification is recommended (administering 3 cycles of BEP and 1 cycle of EP) [34].

• In patients with intermediate and poor prognosis, it is recommended to administer 4 cycles of chemotherapy with the BEP combination (for the regimen, see Appendix A3) to improve patient survival [11,21,24,31].

GPR ALOE 2Grade of Recommendation – A (Level of Evidence – 2).

Comments: Chemotherapy is the mainstay of treatment. The choice of therapy is based on the IGCCCG prognostic classification (see Appendix A3). Risk group assignment is determined by marker levels after orchiectomy. An alternative to the BEP regimen is 4 cycles of the PEI or TIP combination (see Appendix A3). PEI and TIP combinations may be preferred over BEP in patients for whom bleomycin** is undesirable (pulmonary damage due to comorbidities, or patients scheduled for extensive thoracic surgery after completion of chemotherapy).

It is important to keep in mind the differences in dosing of bleomycin** preparations containing the active substances bleomycetin hydrochloride (cumulative dose 60 mg) and bleomycin sulfate (cumulative dose 90 mg) (see Appendix A3).

In patients in a severe general condition due to the extent of the tumor process, with a typical clinical presentation and high levels of AFP or hCG, emergency chemotherapy is permitted without morphological verification of the diagnosis.

3.4.4. Principles of chemotherapy

• All first-line chemotherapy cycles are recommended to be administered every 3 weeks (calculated from the start of the previous chemotherapy course) [31].

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

Comments: The algorithm for dose reduction of chemotherapeutic agents depending on hematological toxicity is presented in Appendix A3. A delay in the scheduled treatment cycle is possible in the presence of active infection or severe thrombocytopenia (platelet count <50,000/μL) on day 1 of the planned cycle (Table 3). The presence of uncomplicated neutropenia, including severe neutropenia (neutrophil count >500/μL), is not a reason to delay the scheduled treatment cycle. The next cycle of BEP chemotherapy may be initiated regardless of the neutrophil count prior to the start of treatment. In patients with poor prognosis according to IGCCCG, the use of colony-stimulating factor preparations from the first cycle of first-line therapy is recommended for primary prophylaxis of febrile neutropenia.

If febrile neutropenia, grade IV neutropenia lasting more than 7 days, or neutropenia complicated by infection was observed during the previous chemotherapy course, prophylactic administration of colony-stimulating factor preparations is recommended for all subsequent chemotherapy courses [31].

• In patients in a severe general condition (3–4 points on the ECOG scale) due to the extent of the tumor process, the 1st cycle of "stabilization" chemotherapy is recommended to be administered in a reduced format (e.g., etoposide** and cisplatin** for 2–3 days) to reduce the incidence of adverse events [11,36].

GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4).

Comments: the administration of the 1st cycle of chemotherapy in such patients is associated with a high incidence of complications (tumor lysis, hemorrhage, infection). This is especially characteristic of metastatic choriocarcinoma when hCG levels exceed 50,000 mIU/mL. For this reason, to stabilize the patient's condition, a 40–60% reduced EP course with fractionated drug administration or carboplatin** monotherapy at AUC 5–7, followed by prophylactic administration of colony-stimulating factor preparations, is recommended as the 1st cycle. After the patient's condition improves, which usually occurs within the 1st week, and blood counts recover, chemotherapy is administered in the full volume planned according to the IGCCCG prognosis.

• When treating patients with non-seminomatous germ cell tumors with intermediate or poor prognosis according to the IGCCCG classification, it is advisable to assess the rate of decline of tumor markers (AFP, hCG, if initially elevated) after the first or second cycle of chemotherapy for prognostic stratification of patients. An unfavorable rate of decline in AFP and/or hCG concentrations may be considered a factor associated with reduced efficacy of first-line therapy and serve as a basis for modifying the treatment [74].

GPR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: the results of randomized trials have demonstrated that an unfavorable decline in tumor marker concentration is associated with a significant increase in the risks of disease progression after first-line chemotherapy in non-seminomatous germ cell tumors. Early chemotherapy intensification may improve progression-free survival without a significant impact on overall survival in this patient population, although the optimal regimen has not yet been defined.

3.4.5. Treatment of patients with brain metastases

• As 1st-line therapy for patients with brain metastases, it is recommended to administer 4 cycles of chemotherapy according to the BEP or PEI program (for regimens, see Appendix A3) to improve patient survival [12,17,37].

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

Comments: Upon achieving a complete response in the brain, further local treatment is not recommended due to its rarity, and the role of local methods (radiation therapy, surgery) for residual brain metastases has not been fully defined. A large retrospective analysis showed that surgery or radiation therapy improved survival only when added to 2nd- and 3rd-line, but not 1st-line, chemotherapy [37].

3.4.6. Response assessment, treatment after completion of chemotherapy

• In patients with non-seminomatous tumors after completion of first-line chemotherapy, it is recommended to surgically resect residual masses measuring ≥1 cm to reduce the risk of relapse and progression [11,38,39].

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

• In patients with residual tumors measuring <1 cm after 2nd- and subsequent-line chemotherapy, the risk of viable malignant tumor cells is significantly higher; therefore, it is recommended to surgically resect all residual tumor masses regardless of size to reduce the risk of relapse and progression [31,40].

GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4).

Comments: the optimal timing for surgical intervention is 4–6 weeks after the completion of chemotherapy. In case of involvement of multiple anatomical regions, surgical treatment begins with the zone of maximum involvement. When performing retroperitoneal lymphadenectomy, it is extremely critical to completely remove all tumor masses to the maximum extent possible. Resection of adjacent organs and tissues, including major vessels, is justified to achieve radicality. When the size of retroperitoneal residual tumor nodes is <5 cm, it is preferable to use modified unilateral templates for retroperitoneal lymphadenectomy, as well as nerve-sparing techniques whenever possible to preserve antegrade ejaculation.

Patients with a complete clinical response or those in whom necrosis or teratoma is found within the resected residual tumor are subject to surveillance. If viable malignant cells are present in the radically resected tumor, 2 cycles of TIP chemotherapy are recommended. In patients with viable malignant cells present in the radically resected tumor after the 2nd and subsequent lines of therapy, postoperative therapy is not recommended.

• In case of complete regression of seminoma or residual metastases measuring <3 cm, it is recommended to perform surveillance for early detection of disease progression [11, 41, 42].

GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4).

• Performing a biopsy of the residual tumor is not recommended due to low diagnostic value [11, 12, 13].

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

• In patients with seminoma residual metastases measuring >3 cm, it is recommended to perform 18F-FDG positron emission tomography combined with computed tomography no earlier than 8 weeks after the completion of chemotherapy to clarify further patient management tactics [11, 41, 42].

GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4).

• If radiopharmaceutical uptake is increased, it is recommended to perform surgical treatment or surveillance; in the absence of uptake, surveillance is recommended to prevent tumor recurrence [11, 41, 42].

GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4).

Comments: the absence of radiopharmaceutical uptake in seminoma residual metastases highly likely indicates a complete pathologic response (it has a high negative predictive value). However, radiopharmaceutical uptake is more frequently caused by reactive inflammation in the tumor following chemotherapy (low positive predictive value). If radiopharmaceutical uptake is present in the residual tumor, surgery is recommended provided it is safe. In situations where resection of the residual tumor carries a high risk of complications (e.g., invasion of major vessels), active surveillance is a viable option.

3.4.7. Treatment of recurrent germ cell tumors

• For relapse chemotherapy, combinations based on ifosfamide** and cisplatin** (TIP, VeIP regimens) or high-dose chemotherapy with hematopoietic stem cell transplantation are recommended to improve patient survival (for regimens, see Appendix A3) [12, 43–45].

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

Comments: the optimal 2nd-line therapy regimen is the TIP regimen, which achieves long-term survival in 25% of patients with non-seminomatous germ cell tumors and in half of patients with seminoma [43, 44]. Alternatives include PEI (especially if the patient did not receive etoposide** in the 1st line of therapy) and VeIP [45]. Usually, 4 cycles are administered. The superiority of one 2nd-line regimen over another has not been proven. High-dose chemotherapy with bone marrow hematopoietic support does not significantly improve treatment outcomes, but it can be used in centers with experience in performing it. The treatment of disease relapses in patients with somatic transformation of a teratoma (into sarcoma, adenocarcinoma, etc.) with normal tumor marker levels (AFP and hCG) is carried out according to the treatment principles of the corresponding morphological variants [46].

• Following the completion of relapse chemotherapy, it is recommended to surgically remove all residual tumor regardless of its size to improve patient survival [12, 31].

GUR CLOE 4Grading of Recommendations Assessment, Development, and Evaluation (GRADE) – C (Level of Evidence – 4).

• In the event of rising tumor marker levels during therapy, exhaustion of chemotherapy options, and tumor localization in a single anatomical region, it is recommended to perform surgical removal of the tumor to improve patient survival [47].

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

Comments: this approach offers a chance to save about 25% of patients, especially those with late relapses, moderately elevated AFP levels, and retroperitoneal localization of the residual tumor. In cases of rapid progression with rising hCG levels, surgical treatment is pointless.

• In late relapses (occurring more than 2 years after the end of chemotherapy), it is recommended to perform radical surgical removal if feasible, to improve patient survival [38, 47].

GGR BERL 3Grade of Recommendations – B (Evidence Level – 3).

Comments: the proportion of late relapses does not exceed 5% of the total number of relapses. A feature of late relapses is low sensitivity to chemotherapy, which allows recommending surgical treatment as the 1st step in potentially resectable tumors even in the presence of elevated tumor marker levels. If radical tumor removal is impossible and tumor marker levels are elevated, it is necessary to initiate 2nd-line chemotherapy followed by surgery.

3.5. Pain management

The principles of analgesia and the optimal choice of pain management therapy in patients with germ cell tumors and chronic pain syndrome correspond to the pain management principles outlined in the clinical guidelines "Chronic Pain Syndrome (CPS) in Adult Patients Requiring Palliative Medical Care".

3.6. Supportive care in patients with germ cell tumors

• Patients are recommended prophylaxis and treatment of venous thromboembolic complications [107–109].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

• Due to the high risk of venous thrombosis in patients with metastatic retroperitoneal lymph node involvement >3.5 cm, unfavorable IGCCCG prognosis in the 1st line of therapy, and/or the presence of a central venous catheter, it is recommended to administer prophylaxis for thromboembolic complications (in the absence of contraindications) [107].

GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4).

Comments: when administering drug prophylaxis for venous thromboembolic complications, high risks of hemorrhagic complications resulting from the effect of antitumor therapy should be taken into account—primarily in patients with high hCG levels, as well as the development of thrombocytopenia in the inter-cycle interval. The use of heparin group drugs (low molecular weight heparins) may be preferred.

Comments: The principles of diagnosis, prevention, and treatment of venous thromboembolic complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Somonova O. V. et al. Thromboembolic Complications [110]. https://rosoncoweb.ru/standarts/?chapter=thromboembolism

• When administering antitumor drug therapy with emetogenic side effects, patients are recommended prophylaxis and treatment of nausea and vomiting [102–103].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: The principles of diagnosis, prevention, and treatment of nausea and vomiting during antitumor drug therapy are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Vladimirova L. Yu. et al. Nausea and Vomiting [104]. https://rosoncoweb.ru/standarts/?chapter=nausea_vomiting

• In patients with bone metastases, it is recommended to provide prophylaxis and treatment of bone complications [105].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: The principles of diagnosis, prevention, and treatment of bone complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Bagrova S. G. et al. Bone Tissue Pathology [106]. https://rosoncoweb.ru/standarts/?chapter=bone_pathology

• During antitumor drug therapy, patients are recommended prophylaxis and treatment of febrile neutropenia and infectious complications [111–113].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of febrile neutropenia and infectious complications, as well as the principles of antibacterial therapy, are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sakaeva D. D. et al. Practical guidelines for the diagnosis and treatment of febrile neutropenia [114]. https://rosoncoweb.ru/standarts/?chapter=febrile_neutropenia

• During antineoplastic drug therapy, patients are recommended to receive correction for hepatotoxicity [115,116].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comments: The principles of diagnosis, prevention, and treatment of hepatotoxicity are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Tkachenko P. E. et al. Hepatotoxicity [117]. https://rosoncoweb.ru/standarts/?chapter=hepatotoxicity

• During antineoplastic drug therapy, patients are recommended to receive prevention and treatment of cardiovascular complications [118-121].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

Comments: The principles of diagnosis, prevention, and treatment of cardiovascular complications during antineoplastic therapy are outlined in the Practical Guidelines of the Russian Society for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Vitsenya M. V. et al. Cardiovascular toxicity [122]. https://rosoncoweb.ru/standarts/?chapter=cardiovascular_toxicity

• During antineoplastic drug therapy, patients are recommended to receive prevention and treatment of dermatological reactions [123,124].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: The principles of diagnosis, prevention, and treatment of skin complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Koroleva I. A. et al. Dermatological reactions [124]. https://rosoncoweb.ru/standarts/?chapter=dermatological_reactions

• To maintain the metabolic reserves of the cancer patient's body and increase their resistance to treatment (surgical, drug, radiation), nutritional support is recommended. The choice of nutritional support method is determined by the various types of nutritional disorders in the patient. Placement of a nasogastric, nasointestinal, percutaneous, endoscopic, laparoscopic, or laparotomic stoma, endoscopic stenting for tumor stenosis, or palliative radiation therapy may be recommended [125,126].

Level of recommendation validity – 1 (level of evidence – A).

Comments: The principles of nutritional support are presented in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sytov A. V. et al. Nutritional support [127]. https://rosoncoweb.ru/standarts/?chapter=nutritional_support

• During antineoplastic drug therapy, patients are recommended to receive prevention and treatment of nephrotoxicity [128-130].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of nephrotoxicity is presented in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Gromova E. G. et al. Nephrotoxicity [131]. https://rosoncoweb.ru/standarts/?chapter=nephrotoxicity

• During antineoplastic drug therapy, patients are recommended to receive prevention and treatment of immune-mediated adverse events [132-135].

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

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of immune-mediated adverse events is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Protsenko S.A. et al. Immune-mediated adverse events [136]. https://rosoncoweb.ru/standarts/?chapter=immunerelated_adverse_events

• During antineoplastic drug therapy, patients are recommended prevention and treatment of mucositis [137,138].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of mucositis is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Semiglazova T.Yu. et al. Mucositis [139]. https://rosoncoweb.ru/standarts/?chapter=mucositis

• Patients are recommended treatment for anemia, which occurs as a symptom of a malignant neoplasm and as an adverse event during antineoplastic drug therapy [140,141].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: The procedure and principles for the prevention and treatment of anemia correspond to the principles set forth in the clinical guidelines "Anemia in malignant neoplasms" (ID: KR624, approval year 2020, www.cr.rosminzdrav.ru) and in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Orlova R.V. et al. Anemia [142].

• During treatment, patients are recommended treatment for anorexia-cachexia syndrome [143].

GOR CLOE 3Grade of Recommendation – C (Level of Evidence – 3).

Comments: A detailed algorithm for the diagnosis and treatment of anorexia-cachexia syndrome is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sytov A.V. et al. Practical guidelines for the treatment of anorexia-cachexia syndrome in cancer patients [144]. https://rosoncoweb.ru/standarts/?chapter=anorexia-cachexia

• When administering cyclic antineoplastic drug therapy involving continuous prolonged (over 6 hours) infusions of antineoplastic agents (fluorouracil**, doxorubicin**, etc.) or in case of poor peripheral vein condition, patients are recommended the use of central venous access and infusion pumps (volumetric infusion pump or pump for metered drug administration) (145).

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: The choice of central access option is determined by the planned duration of the entire treatment course, patient preferences, and anatomical features. For prolonged courses of therapy (over 3 months), the implantation of a subcutaneous venous port system (implantable venous port system, implantable infusion port system) is the most convenient. For shorter periods, a peripherally inserted central venous catheter can serve as an alternative. The principles of central venous access use are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Isyangulova A.Z. et al. Central venous access [146]. https://rosoncoweb.ru/standarts/?chapter=central_venous_access

• During antineoplastic drug therapy, patients are recommended prevention and treatment of antineoplastic drug extravasations. When planning antineoplastic drug therapy, the choice of vascular access is important to prevent extravasation of antineoplastic drugs [147].

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

Comments: Algorithms for vascular access selection, prevention, diagnosis, and treatment of extravasation are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Buydenok Yu.V. et al. Extravasation of antineoplastic drugs [148]. https://rosoncoweb.ru/standarts/?chapter=extravasation_antitumor_drugs

• During antineoplastic treatment, patients are recommended treatment for chronic pain syndrome [149,150].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: Algorithms for the diagnosis and treatment of chronic pain syndrome in cancer patients are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Kogonia L.M. et al. Chronic pain syndrome [150]. https://rosoncoweb.ru/standarts/?chapter=chronic_pain_syndrome

• During antineoplastic drug therapy, patients are recommended prevention and treatment of infusion reactions [151].

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

Comments: Algorithms for the prevention, diagnosis, and management of infusion reactions are detailed in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antineoplastic drug therapy: Orlova R.V. et al. Infusion reactions [152]. https://rosoncoweb.ru/standarts/?chapter=infusion_reactions

• During therapy, patients are recommended monitoring and treatment for reactivation/exacerbation of chronic viral hepatitis [153,154].

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

Comments: Principles of monitoring and management in cancer patients with chronic viral hepatitis are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antineoplastic drug therapy: Feoktistova P.S. et al. Chronic viral hepatitis [154]. https://rosoncoweb.ru/standarts/?chapter=chronic_viral_hepatitis

• During antineoplastic drug therapy, patients are recommended prevention and treatment of neurological complications [155].

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

Comments: Principles of diagnosis, prevention, and treatment of neurological complications of antineoplastic therapy are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antineoplastic drug therapy: Latipova D.Kh. et al. Neurological complications [156]. https://rosoncoweb.ru/standarts/?chapter=neurological_complication

• During antineoplastic hormone therapy, patients are recommended prevention and treatment of hormone-mediated adverse events [157,158].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comments: Principles of diagnosis, prevention, and treatment of hormone-mediated adverse events are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antineoplastic drug therapy: Stenina M.B. et al. Hormone-mediated adverse events [159]. https://rosoncoweb.ru/standarts/?chapter=hormone-mediated_side_events

3.7. Diet therapy

Based on correlation studies, a hypothesis has been proposed regarding the role of diet, particularly the consumption of animal fats, in the etiology of germ cell tumors in men.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Currently, clinical studies involving patients with germ cell tumors are lacking for most types of medical rehabilitation. These recommendations are based on the fact that numerous studies, including meta-analyses (Steffens D. et al. 2018, etc.) and systematic reviews (Nicole L. Stout et al., 2017 and R. Segal et al., 2017, etc.), have proven that various types of medical rehabilitation significantly accelerate functional recovery, shorten hospital stays after surgery, and reduce the incidence of complications and mortality in patients with other malignant neoplasms

4.1. Pre-rehabilitation

• Patients with germ cell tumors are recommended to undergo pre-rehabilitation, if indicated, including therapeutic exercise (physical therapy), psychological and nutritional support, and patient education to accelerate functional recovery, shorten postoperative hospital stays, and reduce the incidence of complications and mortality [58].

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

• Patients with germ cell tumors are recommended to increase physical activity 2 weeks prior to surgery in order to shorten hospital stay, reduce the risk of postoperative complications, and improve postoperative quality of life [59].

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

• Patients with germ cell tumors are recommended, if indicated, to undergo respiratory muscle training during pre-rehabilitation prior to surgical treatment, in patients at high risk for pulmonary complications, to reduce the frequency of postoperative pulmonary complications and shorten hospital stay [60].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

• Patients with germ cell tumors are recommended, if indicated, to undergo neuropsychological rehabilitation during pre-rehabilitation prior to planned surgical treatment to improve mood, reduce anxiety and depression, and improve adaptation to daily life after surgery [61].

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

4.2. Rehabilitation Following Surgical Treatment

4.2.1. First stage of rehabilitation in surgical treatment

• Patients with germ cell tumors are recommended a multidisciplinary approach to postoperative pain management, potentially incorporating physical rehabilitation (exercise therapy), positioning, clinical and psychological pain management (relaxation), transcutaneous electrical nerve stimulation, and acupuncture to improve treatment outcomes [62].

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

• Patients with germ cell tumors are recommended the use of fast-track rehabilitation tactics and ERAS (early rehabilitation after surgery) programs in the postoperative period to improve treatment outcomes [63].

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

• Patients with germ cell tumors are recommended a multidisciplinary approach in the rehabilitation of patients after surgical treatment, including motor rehabilitation, psychological support, and occupational therapy (interaction with occupational therapists) to improve treatment outcomes [60,64].

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

• Patients with germ cell tumors are recommended early mobilization and activation after surgical treatment to improve functional capabilities in the early postoperative period [65].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• Patients with germ cell tumors are recommended an early start of recovery treatment after surgery, as it improves functional outcomes [66].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• Patients with germ cell tumors are recommended, following surgery and if indicated, to combine positioning, exercise therapy, cryotherapy to the surgical area, general medical massage, and electrotherapy for pain relief [67].

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

4.2.2. Second stage of rehabilitation in surgical treatment

• Patients with germ cell tumors are recommended, following surgery, to use techniques aimed at scar management to prevent the formation of coarse scar changes, including in the deep layers of soft tissues: deep massage, stretching exercises, and ultrasound therapy [69].

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

• Patients with germ cell tumors are recommended, in the event of lymphedema, to undergo therapy including general medical massage (manual lymphatic drainage), wearing compression garments, exercise therapy, and skin care to eliminate edema syndrome [70].

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

4.2.3. Third stage of rehabilitation in surgical treatment

• Patients with germ cell tumors are recommended, following surgery, to perform and gradually expand an exercise therapy regimen including aerobic load, which improves the outcomes of combined treatment for malignant neoplasms and quality of life [71].

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

• Patients following surgery recommend general medical massage to improve quality of life and reduce the severity of pain and fatigue [72]

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

4.3. Rehabilitation During Chemotherapy

• Patients with germ cell tumors are recommended, if indicated, to start physical exercise early during chemotherapy, which helps prevent muscle weakness, hypotrophy, and reduced exercise tolerance [73].

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

• Patients with germ cell tumors are recommended, if indicated, to engage in exercise therapy during chemotherapy, which helps reduce the severity of fatigue and depression. Combining exercise therapy with psychological support in correcting fatigue and depression during chemotherapy is more effective than pharmacological intervention alone [75].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

• Patients with germ cell tumors are recommended to individually tailor the volume and intensity of exercise therapy during chemotherapy based on the degree of fatigue (mild, moderate, severe), and to increase exercise intensity as general condition improves. It is recommended to combine aerobic and resistance training [73].

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

• Patients with germ cell tumors are recommended, if indicated, a course of massage for 6 weeks after the start of chemotherapy, which reduces fatigue during combined treatment [76].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

• Patients with germ cell tumors are recommended, if indicated, to perform balance training exercises, which are more effective for correcting polyneuropathy than a combination of endurance and strength exercises [77].

GoR BGrade of Recommendation – B (Level of Evidence – 3).

• Patients with germ cell tumors are recommended a 6-week course of terrain therapy (walking therapy), if indicated, for patients with germ cell tumors and chemotherapy-induced peripheral neuropathy as part of the general rehabilitation program to control clinical manifestations of neuropathy [78].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

• Patients with germ cell tumors are recommended low-intensity laser therapy, if indicated, for the treatment of chemotherapy-induced peripheral neuropathy [79].

LoR CLE 2Level of Recommendation – C (Level of Evidence – 2).

• Patients with germ cell tumors are recommended low-frequency magnetotherapy, if indicated, for the treatment of chemotherapy-induced peripheral neuropathy [80].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

• Patients with germ cell tumors are recommended percutaneous electrical nerve stimulation (TENS) for 20 minutes a day for 4 weeks, if indicated, for the treatment of chemotherapy-induced neuropathy [81].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• Patients with germ cell tumors are recommended low-intensity laser radiation therapy to the oropharynx and gingiva area, if indicated, for the prevention of chemotherapy-induced oral mucositis [82].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

• Patients with germ cell tumors are recommended physical therapy exercises, if indicated, which reduces the incidence of cardiac complications during chemotherapy [83].

OGR CELR 5Level of Evidence – C (level of reliability of evidence – 5).

• Patients with germ cell tumors are recommended the use of a scalp cooling system, if indicated, to prevent chemotherapy-induced alopecia [84].

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

4.4. Rehabilitation During Radiation Therapy

• Patients with germ cell tumors are recommended a complex of physical therapy exercises (aerobic exercise combined with strength training) during radiotherapy, if indicated, which helps prevent fatigue and improves quality of life [85].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

• Patients with germ cell tumors are recommended physical therapy exercises, if indicated, which increases bone density and endurance during radiotherapy, primarily in patients with bone metastases [85].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

• Patients with germ cell tumors are recommended low-intensity laser skin irradiation starting 3 days after the initiation of radiotherapy, 3 days a week, if indicated, for the prevention of radiation dermatitis [86].

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

4.5. Principles of psychological rehabilitation of patients with germ cell tumors

• Patients with germ cell tumors are recommended to be informed about the disease, psychological reactions, their area of responsibility during treatment, methods of communication with relatives and medical staff, ways to obtain additional information about their disease or condition, and ways to obtain social support, which leads to an improved quality of life and treatment outcome [87-89].

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

• Patients with germ cell tumors are recommended to achieve a combined effect of coping behavior and perceived social support, which leads to fewer intrusive and avoidant thoughts before treatment and ensures better psychological adaptation 1 month after treatment [90,91].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

5. Prevention and Dispensary Observation

• Given the high curability of germ cell tumors and the long life expectancy of patients, it is recommended to prevent and early diagnose late complications of chemotherapy (cardiovascular diseases, metabolic syndrome, hypogonadism, infertility, pulmonary toxicity, etc.) involving relevant subspecialists [92].

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

5.1. Follow-up for stage I non-seminoma under active surveillance (no chemotherapy administered)

5.2. Surveillance for patients with stage I seminoma

• Modern research data indicate that using a streamlined follow-up schedule provides sufficient tumor control rates and early relapse detection, therefore the following follow-up schedule may be recommended:

  physical examination, chest X-ray, tumor markers (serum AFP, hCG levels, blood LDH activity) – every 3 months for 2 years, every 4 months for the third year, then every 6 months until the end of the 6-year follow-up period (X-ray may be performed at every second visit);

  Computed tomography of the abdomen and retroperitoneum with intravenous bolus contrast or magnetic resonance imaging of the abdomen with intravenous contrast – at 6, 18, and 36 months from completion [12,31,99].

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

5.3. Surveillance for patients after chemotherapy

6. Organization of Medical Care

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

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

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

3) based on these clinical guidelines;

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

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

If a testicular, retroperitoneal, or mediastinal neoplasm is detected or suspected in a patient, general practitioners, district general practitioners, family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the prescribed manner for a consultation to an outpatient oncological care center, a primary oncological office, or a primary oncological department of a medical organization to receive primary specialized health care.

Consultation at the outpatient oncological care center, primary oncological office, or primary oncological department of a medical organization must be held no later than 5 working days from the date of issuance of the referral. The oncologist of the outpatient oncological care center (in the absence of an outpatient oncological care center, the oncologist of the primary oncological office or primary oncological department) shall arrange for the acquisition of biopsy (surgical) material (except for testicular neoplasms) and arrange for other diagnostic tests necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

If it is impossible to obtain biopsy (surgical) material or perform other diagnostic tests in the medical organization that includes the outpatient oncological care center (primary oncological office, primary oncological department), the patient shall be referred by the attending physician to an oncological dispensary or a medical organization providing medical care to patients with germ cell tumors.

The timeframe for pathomorphological examinations necessary for the morphological verification of a germ cell tumor must not exceed 15 working days from the date the biopsy (surgical) material arrives at the pathoanatomical bureau (department).

If a germ cell tumor is detected or suspected in a patient during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with germ cell tumors to determine the management strategy and the need for specialized antitumor treatment methods.

An oncologist at an outpatient oncological care center (primary oncological office, primary oncological department) refers the patient to an oncological dispensary or to medical organizations providing medical care to patients with germ cell tumors to clarify the diagnosis (if the diagnosis, including the extent of the oncological process and the stage of the disease, cannot be established by the oncologist of the outpatient oncological care center, primary oncological office, or primary oncological department) and to receive specialized, including high-tech, medical care.

The timeframe for initiating specialized, excluding high-tech, medical care for patients with germ cell tumors in a medical organization providing medical care to patients with germ cell tumors must not exceed 14 calendar days from the date of morphological verification of the germ cell tumor or 14 calendar days from the date of establishing a provisional diagnosis of a germ cell tumor (if there are no medical indications for pathological and anatomical examinations in an outpatient setting).

Specialized, including high-tech, medical care is provided by oncologists and radiotherapists in an oncological dispensary or in medical organizations providing medical care to patients with germ cell tumors that hold the required license, have the necessary material and technical base, and employ certified specialists, in inpatient and day-patient settings, and includes the prevention, diagnosis, and treatment of germ cell tumors requiring the use of special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing medical care to patients with germ cell tumors, the medical examination and treatment strategy is determined by a concilium of oncologists, involving other medical specialists if necessary. The decision of the concilium of physicians is documented in a protocol, signed by the concilium participants, and entered into the patient's medical records.

Chemotherapy for patients with advanced stages of germ cell tumors must be performed in institutions with sufficient experience in administering it (at least 5 patients with poor prognosis according to IGCCCG per year). If it is impossible to perform chemotherapy in the aforementioned institution, it should be carried out in an oncological dispensary after the treatment strategy is determined by a specialist from a center with such experience (in person or via telemedicine consultation).

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

For the surgical removal of a residual tumor after chemotherapy (except for post-chemotherapy retroperitoneal lymph node dissection), the patient is referred to a specialized or federal center with sufficient experience in such interventions (at least 10 surgical interventions per year).

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

1) the presence of complications of a germ cell tumor requiring specialized emergency and urgent medical care;

2) the presence of complications resulting from the treatment (surgery, radiation therapy, drug therapy, etc.) of a germ cell tumor.

Indications for planned hospitalization in a medical organization are:

1) the need to perform complex interventional diagnostic medical procedures requiring subsequent monitoring in an inpatient or day-hospital setting;

2) the presence of indications for specialized antitumor treatment (surgery, radiation therapy, including contact, external beam, and other types, drug therapy, etc.) requiring monitoring in a 24-hour or day hospital setting.

Indications for discharging a patient from a medical organization are:

1) completion of a course of treatment or one of the stages of specialized, including high-tech, medical care in a 24-hour or day hospital setting in the absence of treatment complications requiring drug correction and/or medical interventions in an inpatient setting;

2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in a 24-hour or day hospital setting prescribed by the concilium of the oncological medical organization, in the absence of complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting;

3) the need to transfer the patient to another medical organization according to the relevant medical profile.

The conclusion on the feasibility of transferring the patient to a specialized medical organization is drawn up after a preliminary consultation based on the provided medical documents and/or a preliminary examination of the patient by specialist physicians of the medical organization to which the transfer is planned.

7. Additional Information

Known prognostic factors for stages IS, II, and III TNM testicular germ cell tumors, primary retroperitoneal and mediastinal tumors, which are recommended to be recorded, are presented in Table 2.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Kaprin Andrey Dmitrievich, Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Honored Physician of the Russian Federation, General Director of the National Medical Research Radiological Center, Head of the Department of Urology and Operative Nephrology with a Course in Oncourology at the Medical Institute of the Peoples' Friendship University of Russia (Moscow, Russia).

2. Matveev Vsevolod Borisovich, Corresponding Member of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, Deputy Director for Scientific and Innovative Work and Head of the Urological Department at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, President of the Russian Society of Oncourologists.

3. Alekseev Boris Yakovlevich, Doctor of Medical Sciences, Professor, Deputy Director for Science at the National Medical Research Radiological Center of the Russian Ministry of Health.

4. Pushkar Dmitry Yurievich, Corresponding Member of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Head of the Department of Urology at the A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health (Moscow, Russia), Chief Urologist of the Russian Ministry of Health, Russian Society of Urology.

5. Govorov Alexander Viktorovich, Doctor of Medical Sciences, Professor at the Department of Urology, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health (Moscow, Russia), Russian Society of Urology.

6. Gorban Nina Andreevna, Candidate of Medical Sciences, Head of the Center for Pathomorphology and Molecular Genetic Diagnostics at the Central Clinical Hospital with Policlinic of the Executive Office of the President of the Russian Federation, Russian Society of Pathological Anatomy.

7. Kirichek Andrey Andreevich, Assistant at the Department of Surgical Diseases with a Course in Oncology at the F.P. Haase Moscow Medical and Social Institute, Oncologist at Moscow Clinical Oncology Hospital No. 62 (Moscow, Russia), Russian Society of Oncourologists.

8. Tryakin Alexey Alexandrovich, Doctor of Medical Sciences, Deputy Director for Scientific Work (Research Institute of Clinical Oncology), Head of the Department of Antitumor Drug Therapy No. 2 of the Drug Therapy Department at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the Russian Society of Clinical Oncology.

9. Tyulyandin Sergey Alekseevich, Doctor of Medical Sciences, Professor, Chief Researcher at the Department of Antitumor Drug Therapy No. 2 of the Drug Therapy Department at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Chairman of the Russian Society of Clinical Oncology.

10. Moiseenko Vladimir Mikhailovich, Doctor of Medical Sciences, Honored Physician of the Russian Federation, laureate of the Russian Government Prize, Director of the St. Petersburg Clinical Research and Practical Center for Specialized Medical Care, Chief Freelance Oncologist-Chemotherapist of St. Petersburg, Member of the Russian Society of Clinical Oncology.

11. Semenova Anna Igorevna, …. N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health (St. Petersburg).

12. Fedyanin Mikhail Yurievich, Doctor of Medical Sciences, Head of the Chemotherapy Service at the Kommunarka Moscow Multidisciplinary Clinical Center.

13. Rumyantsev Alexey Alexandrovich, Candidate of Medical Sciences, Head of the Department of Antitumor Drug Therapy No. 2 of the Drug Therapy Department at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

14. Volkova Maria Igorevna, Doctor of Medical Sciences, Professor, Leading Researcher at the Department of Oncourology at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

15. Gladkov O.A., Doctor of Medical Sciences, Professor, Honored Physician of the Russian Federation, EVIMED LLC (Chelyabinsk).

16. Kostin Andrey Alexandrovich, Deputy General Director for Science at the National Medical Research Radiological Center of the Russian Ministry of Health

17. Khmelevsky Evgeny Vitalievich, Head of the Department of Radiation Therapy at the P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

18. Fedenko Alexander Alexandrovich, Head of the Department of Drug Treatment of Tumors at the P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

19. Bolotina Larisa Vladimirovna, Head of the Chemotherapy Department at the Department of Drug Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

20. Natalia A. Falaleeva, Head of the Department of Drug Treatment of Malignant Tumors, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

21. Elena V. Filonenko, Head of the Center for Laser and Photodynamic Diagnostics and Therapy of Tumors, P.A. Herzen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health

22. Kirill M. Nyushko, PhD, Leading Researcher, Department of Oncourology, P.A. Herzen Moscow Oncology Research Institute

Medical Care Organization Section

1. Aleksey A. Nevolskikh, MD, Deputy Director for Therapeutic Work, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

2. Sergey A. Ivanov, Professor of the RAS, MD, Director of the A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

3. Zhanna V. Khaylova, PhD, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

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

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1) oncologists;

2) urologists;

3) radiologists;

4) radiation therapists;

5) surgeons;

6) anesthesiologists-reanimatologists;

7) general practitioners (physicians);

8) general practice physicians (family physicians);

9) neurologists;

10) pediatric oncologists;

11) geneticists;

12) pathologists;

Methods used for collecting/selecting evidence: search in electronic databases; analysis of current scientific developments on the problem of germ cell tumors in Russia and abroad; synthesis of practical experience of Russian and foreign specialists.

Levels of evidence trustworthiness in accordance with the methodological recommendations for the development and updating of clinical guidelines (Order of the Russian Ministry of Health No. 103n dated February 28, 2019)

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Levels of evidence trustworthiness with the indication of the applied classification of levels of evidence trustworthiness (LET)

Table 3. Grades of recommendation (GR) with the indication of the applied classification of grades of recommendation

Methods used for formulating recommendations: expert consensus.

Economic analysis. Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Method of recommendation validation:

• external expert review;

• internal expert review.

Description of the guideline validation method. The preliminary version of these guidelines was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the guidelines is accessible for understanding.

Comments were received from primary care oncologists and urologists regarding the clarity of the presentation of the guidelines and their assessment of the importance of the guidelines as a working tool in 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 expert review. The draft guidelines 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 guidelines.

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.

Updates of clinical guidelines: updating is carried out at least once every 3 years, taking into account new information regarding the diagnosis and management of men with germ cell tumors, but no more frequently than once every 6 months. The decision to update is made by the Ministry of Health of the Russian Federation based on proposals submitted by medical professional non-profit organizations. The generated proposals must take into account the results of a comprehensive assessment of medicinal products 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.

Appendix A3. Reference Materials

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

Chemotherapy regimens used in the treatment of germ cell tumors [12]

¹ Cisplatin** administration is carried out against the background of intravenous hydration with normal saline (total daily volume 2.5 L), necessary to maintain diuresis >100 ml/h during cisplatin** administration and for the subsequent 3 h.

² Mesna** is used at a daily dose of 100% of the ifosfamide** dose, divided into 3 administrations throughout the day: immediately before ifosfamide**, and then 4 and 8 hours after the start of its infusion.

³ The active substances bleomycetin hydrochloride (isomer A5) and bleomycin sulfate (a mixture of isomers A2 and B2) are not identical medicinal products. When using bleomycin sulfate in the BEP regimen, doses of 30 mg are used on days 1, 3, 5 (or 1, 8, 15). When using the less studied bleomycetin hydrochloride, it is recommended to use course doses of the drug that are 30–40% lower, for example, 30 mg on days 1 and 5 [12].

⁴ Rounding the single dose of filgrastim** to 300 or 480 mcg is permitted. The duration of therapy is determined by the rate of neutrophil recovery, but should not be less than 5 days [93].

Chemotherapy dose reduction algorithm based on hematological toxicity* [15]

* Determined based on test results on the day of the start of the next chemotherapy cycle.

** In certain situations, starting the next treatment course with colony-stimulating factor support without delay is possible in the absence of evidence of active infection

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Recommendation for chemotherapy complications: repeat appointment (examination, consultation) with an oncologist, implementation of the specialist physician's prescriptions.

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

Appendix G1. WHO/ECOG Patient Performance Status Scale

Russian title: WHO/ECOG Performance Status Scale.

Original title: The Eastern Cooperative Oncology Group/World Health Organization Performance Status (ECOG/WHO PS).

Source (official developer website, validation publication): https://ecogacrin.org/resources/ecog-performance-status.

Oken M.M., Creech R.H., Tormey D.C. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649–55.

Type: rating scale

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

Content (template):

Note. The key (interpretation) is provided within the scale itself.