Cancers of Unknown Primary: Clinical Practice Guidelines

List of Abbreviations

ALT - alanine aminotransferase

AST - aspartate aminotransferase

AFP - alpha-fetoprotein

PST - primary site identified

G-CSF - colony-stimulating factors

IHC - immunohistochemical examination

ICC - immunocytochemical examination

CT - computed tomography

LDH - lactate dehydrogenase

RT - radiotherapy

MRI - magnetic resonance imaging

AEs - adverse events

NSE - neuron-specific enolase

CUP - carcinoma of unknown primary

PSA - prostate-specific antigen

PET - positron emission tomography

PET-CT - positron emission tomography combined with CT (Whole-body positron emission tomography with tumor-tropic radiopharmaceuticals)

BC - breast cancer

LC - liver cancer

RP - radiopharmaceuticals for the diagnosis of neoplasms (Fludeoxyglucose [18F])

CEA - carcinoembryonic antigen

RF - Russian Federation

OC - ovarian cancer

US - ultrasound

FN - febrile neutropenia

hCG, β-hCG - human chorionic gonadotropin

ALP - alkaline phosphatase

EGD - esophagogastroduodenoscopy

ECOG - Eastern Cooperative Oncology Group performance status scale

ER/ER - estrogen receptors

ERAS - early rehabilitation after surgery

ESMO - European Society for Medical Oncology

NCCN - National Comprehensive Cancer Network (USA)

PR/PR - progesterone receptors

18F-FDG Fludeoxyglucose [18F]** - vital and essential drugs

Terms and Definitions

Supportive care - prevention and treatment of complications resulting from both the malignant disease and anticancer treatment. Correction of these conditions includes the restoration of physical and psychological functions throughout anticancer treatment, as well as during the rehabilitation period.

Prehabilitation - rehabilitation from the moment of diagnosis until the start of treatment (surgical treatment/chemotherapy/radiotherapy).

First phase of rehabilitation – rehabilitation during the specialized treatment period of the underlying disease (including surgical treatment / chemotherapy / radiation therapy) in departments of medical organizations tailored to the profile of the underlying disease.

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, the period of residual effects of the disease in departments (offices) of rehabilitation, physiotherapy, exercise therapy, reflexology, manual therapy, psychotherapy, medical psychology providing medical care on an outpatient basis, in day hospitals, as well as by mobile teams at home (including in sanatorium-resort organizations), and speech therapy (defectology) offices.

In the case of rehabilitation of cancer patients, the tactics of restorative treatment and the choice of its methods are not tied to the timing of hospitalization. The use of hydrotherapy and balneotherapy is not excluded at the second and third stages of rehabilitation.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Tumors of unknown primary site (CUP) - a disease manifested by metastatic tumors, while the primary site cannot be established either on the basis of anamnesis or according to examination data [1].

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

Due to high tumor heterogeneity, it is usually impossible to determine which cell clone is the source of metastasis, since the biopsy (surgical) material lacks a set of morphological features that allow distinguishing cells by their organ of origin [2-4]. On average, the primary source is identified during life in only 25% of patients. In 15–20% of cases, the primary site is not found even at autopsy [5, 6]. Although CUPs differ in their origin from various organs, their biological behavior is approximately the same. They are often characterized by a random, atypical localization (i.e., involvement of non-regional lymph nodes), as well as rapid progression of the process at the very early stages of development.

1.3 Epidemiology of the Disease or Condition

According to various authors, patients with CUP account for 3 to 5% of cancer patients seeking medical care [7–9]. In pediatric practice, CUP accounts for less than 1% of all solid tumors [78].

CUP in adults ranks 7th in incidence and 4th in mortality among all malignant neoplasms [6, 10, 11]. CUP occurs with approximately equal frequency in men and women. With increasing age, the incidence curve rises sharply, peaking at 65 years [5, 8, 12].

1.4 Features of Coding the Disease or Condition

Malignant neoplasms of ill-defined, secondary and unspecified sites (C76–C80, D37-D48).

Malignant neoplasm of other and ill-defined sites (C76):

C76.0 - Head, face and neck.

C76.1 - Thorax.

C76.2 - Abdomen.

C76.3 - Pelvis.

C76.4 - Upper limb.

C76.5 - Lower limb.

C76.7 - Other specified and ill-defined sites.

C76.8 - Overlapping lesion of other and ill-defined sites.

Secondary and unspecified malignant neoplasm of lymph nodes (C77):

C77.0 - Lymph nodes of head, face and neck.

C77.1 - Intrathoracic lymph nodes.

C77.2 - Intra-abdominal lymph nodes.

C77.3 - Axillary and upper limb lymph nodes, thoracic lymph nodes.

C77.4 - Inguinal and lower limb lymph nodes.

C77.5 - Intrapelvic lymph nodes.

C77.8 - Lymph nodes of multiple regions.

C77.9 - Lymph node of unspecified site.

Secondary malignant neoplasm of respiratory and digestive organs (C78):

C78.0 - Secondary malignant neoplasm of lung.

C78.1 - Secondary malignant neoplasm of mediastinum.

C78.2 - Secondary malignant neoplasm of pleura.

C78.3 - Secondary malignant neoplasm of other and unspecified respiratory organs.

C78.4 - Secondary malignant neoplasm of small intestine.

C78.5 - Secondary malignant neoplasm of large intestine and rectum.

C78.6 - Secondary malignant neoplasm of retroperitoneum and peritoneum.

C78.7 - Secondary malignant neoplasm of liver.

C78.8 - Secondary malignant neoplasm of other and unspecified digestive organs.

Secondary malignant neoplasm of other sites (C79):

C79.0 - Secondary malignant neoplasm of kidney and renal pelvis.

C79.1 - Secondary malignant neoplasm of bladder, other and unspecified urinary organs.

C79.2 - Secondary malignant neoplasm of skin.

C79.3 - Secondary malignant neoplasm of brain and cerebral meninges.

C79.4 - Secondary malignant neoplasm of other and unspecified parts of nervous system.

C79.5 - Secondary malignant neoplasm of bone and bone marrow.

C79.6 - Secondary malignant neoplasm of ovary.

C79.7 - Secondary malignant neoplasm of adrenal gland.

C79.8 - Secondary malignant neoplasm of other specified sites.

C79.9 - Secondary malignant neoplasm of unspecified site

Malignant neoplasm without specification of site (C80).

C80.0 - Malignant neoplasm, primary site unknown.

C80.9 - Malignant neoplasm of unspecified primary site.

Neoplasms of uncertain or unknown behavior (D37-D48).

D37.9 - Digestive organs, unspecified.

D48.7 - Other specified sites.

D48.9 - Neoplasm of uncertain or unknown behavior, unspecified.

1.5 Classification of the disease or condition

Metastatic tumors with unknown primary site represent the most heterogeneous and diagnostically challenging group of malignant neoplasms. Current morphological and immunohistochemical (IHC) diagnostic methods make it possible to clarify the line of differentiation of a metastatic tumor and/or its organ origin in 75–85% of cases [1]. In the structure of cancer of unknown primary (CUP) in adults, metastases of various types of carcinomas occupy a dominant position, accounting for about 78–80% of all cases; lymphomas and melanoma take second and third place, accounting for 12% and 6%, respectively. Among the rarest metastatic neoplasms are germ cell tumors, sarcomas, and paraganglioma. In turn, the extensive group of metastatic carcinomas is subdivided into adenocarcinomas (60% of cases), poorly differentiated and undifferentiated carcinomas (33% of cases), non-keratinizing squamous cell carcinoma (5% of cases), neuroendocrine tumors and carcinomas (about 2% of cases) [1–7]. The majority of CUP diagnosed in children are of mesenchymal and neuroectodermal origin and are represented by metastases of neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma [77]

The use of cytogenetic research methods aimed at detecting mutations in specific genes (EGFR, BRAF, KRAS, ALK, ROS1, etc.), combined with IHC diagnostics, can increase the tumor type verification rate to 85–90% [13, 14, 15].

International Histological Classification. According to the histological structure of CUP, in accordance with the recommendations of ESMO (European Society for Medical Oncology, 2015), it is advisable to divide them into the following groups [16]:

1. well-differentiated and moderately differentiated adenocarcinomas;

2. poorly differentiated carcinomas;

3. squamous cell carcinoma;

4. undifferentiated tumor;

5. carcinoma with neuroendocrine differentiation.

Patients with tumors of other histological types, despite the absence of a primary focus, should be examined and treated in accordance with the recommendations for this type of tumor.

Staging. There is currently no universally accepted staging system for CUP metastases. Since the disease manifests with metastases at the initial stages, we can speak of a primarily disseminated process which, by the time the patient seeks medical attention, generally extends beyond the organ of origin.

1.6 Clinical presentation of the disease or condition

Clinical manifestations of the disease are nonspecific and depend on the localization of metastatic lesions and the extent of the tumor process.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition: e.g., based on pathognomonic data:

1. anamnestic data,

2. physical examination,

3. laboratory tests,

4. instrumental examination,

5. lifetime pathomorphological and genetic studies (pathological examination of biopsy (surgical) material using immunohistochemical methods

6. additionally – comprehensive genomic sequencing (the service is not covered by compulsory medical insurance (CHI)).

2.1 Complaints and Anamnesis

2.2 Physical Examination

2.3 Laboratory Diagnostics

- Complete blood count (CBC);

- general clinical blood chemistry (total protein, glucose, bilirubin, creatinine, urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), calcium, potassium, sodium), determination of serum C-reactive protein level;

- urinalysis:

- coagulogram (screening hemostasis test), including evaluation of activated partial thromboplastin time (APTT), blood fibrinogen level, international normalized ratio (INR), prothrombin (thromboplastin) time in blood or plasma, and blood D-dimer concentration)

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

- assay of serum human chorionic gonadotropin (free beta-subunit) and serum alpha-fetoprotein (AFP) in individuals under 50 years of age with enlarged mediastinal lymph nodes and under 65 years of age with enlarged retroperitoneal lymph nodes;

- assay of serum human chorionic gonadotropin (free beta-subunit) (beta-hCG) in women of reproductive age with a history of at least one pregnancy, regardless of its outcome and time elapsed;

- Assay of pregnancy-associated plasma protein A (PAPP-A) in blood serum – in case of liver involvement;

- Assay of free prostate-specific antigen (PSA) in blood – in men over 40 years of age;

- Assay of CA 125 tumor marker in blood (CA125) – in women with chest organ involvement, pleural effusion or ascites, retroperitoneal tumor, or inguinal lymph node involvement;

- Assay of CA 19-9 tumor marker in blood (CA-19.9) – when primary pancreatic or biliary tract cancer is suspected;

- Assay of carcinoembryonic antigen (CEA) (A08.30.002 Immunocytochemical study using monoclonal antibodies on material from various tissues and organs to detect tumor metastases (tumor markers: cytokeratins, nm23, SCC, CEA, and others) – when primary colorectal cancer is suspected;

- Assay of neuron-specific enolase (NSE) in blood, blood ferritin, urinary vanillylmandelic acid, and urinary homovanillic acid – when neuroblastoma is suspected;

- Cytological examination (A08.30.003 Cytological examination of punctates and touch imprints of retroperitoneal tumors / A08.30.031 Cytological examination of peritoneal fluid) – in the presence of ascites or a retroperitoneal tumor.

- Bone marrow aspiration cytology (myelogram) for pediatric patients with CUP of mesenchymal and neuroectodermal origin [74-76]

- CYFRA-21-1 assay – when primary thyroid or thoracic cancer is suspected;

- Assay of CA 15-3 tumor-associated marker in blood – when primary breast cancer is suspected;

- Determination of chromogranin A in blood, assay of serotonin, its precursors, and metabolites in blood – when neuroendocrine tumor (NET) metastases of unknown primary are suspected.

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

2.4 Instrumental Diagnostics

Patients with suspected cancer of unknown primary are recommended to undergo the following diagnostic procedures:

If there are contraindications to contrast enhancement during CT or MRI, positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals (PET-CT) is recommended [49].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• In case of unclear or ambiguous results of contrast-enhanced computed tomography of the chest, contrast-enhanced computed tomography of the abdomen and retroperitoneum, contrast-enhanced spiral computed tomography of the pelvis in women, and contrast-enhanced spiral computed tomography of the pelvis in men, it is recommended to consider PET-CT as a secondary diagnostic modality [50].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• If CT or MRI is not feasible, in order to determine the extent of the tumor process, it is recommended to perform targeted chest X-ray, comprehensive abdominal ultrasound, and comprehensive pelvic ultrasound (transvaginal and transabdominal) [50].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• In the presence of morphologically verified squamous cell carcinoma involving supraclavicular lymph nodes and/or adenocarcinoma with metastatic involvement of cervical, supraclavicular, and axillary lymph nodes, it is recommended to perform computed tomography of the facial skull, computed tomography of the upper respiratory tract and neck, or magnetic resonance imaging of the facial skull and neck to verify the potential primary tumor site [51,52].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comment: in widespread metastatic disease, the use of positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals (PET-CT) is limited and performed according to clinical necessity due to difficulties in identifying the primary lesion among multiple metastatic foci.

According to National Comprehensive Cancer Network (NCCN) guidelines, PET-CT is not recommended as a primary diagnostic test [49]. However, there are favorable subgroups for this type of examination: limited or solitary metastases, as well as metastases of squamous cell carcinoma in cervical lymph nodes. In such patients, PET-CT can alter treatment tactics in 30–35% of cases.

Performing 18F-FDG PET-CT is impractical in signet-ring cell gastric cancer, mucinous tumors, hepatocellular carcinoma, clear cell renal cell carcinoma, well- and moderately differentiated neuroendocrine tumors, and prostate cancer due to their low or absent metabolic activity [18, 20, 23, 25, 29].

Patients with suspected or histologically verified well- and moderately differentiated neuroendocrine CUP are recommended to undergo PET-CT with tumor-tropic radiopharmaceuticals [24].

• To verify the potential primary tumor site in case of elevated beta-human chorionic gonadotropin (β-hCG) or alpha-fetoprotein (AFP), it is recommended to perform scrotal ultrasound in men [21].

LoR CLevel of Recommendation - C (Level of Evidence - 5)

• To search for the primary lesion in women over 40 years of age, mammography is recommended in women with involvement of axillary, supra-/subclavicular, mediastinal, retroperitoneal lymph nodes, liver, brain, bones, or multiple lesion sites [15, 16, 19].

LoR CLevel of Recommendation - C (Level of Evidence - 5)

• When primary tumor localization in the urinary bladder is suspected, cystoscopy is recommended [29].

LoR CLevel of Recommendation - C (Level of Evidence - 5)

• Based on clinical indications, it is recommended to perform endoscopic examination of the upper aerodigestive tract and colonoscopy [15-17];

LoR CLoE 5Level of Recommendation - C (Level of Evidence - 5)

• To assess the extent of the malignant process, as well as for differential diagnosis between osteoporosis and a malignant process in metastatic bone lesions, it is recommended to perform whole-body scintigraphy with tumor-tropic radiopharmaceuticals and X-ray control of suspicious areas [30].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comment: performing scintigraphy during PET-CT is impractical [19, 20, 22, 23].

Comment: if brain MRI is not feasible, contrast-enhanced brain CT may be performed.

• To verify the primary site, it is recommended to perform core needle biopsy of superficial tumors, enlarged lymph nodes under visual control, or (if necessary) ultrasound guidance [8, 15-17, 19, 22, 23]

LoR CLevel of Recommendation - C (Level of Evidence - 5)

• To detect/rule out atypical cells in pediatric patients with cancer of unknown primary site (CUP), it is recommended to perform bone marrow core needle biopsy [72]

CGR CLOE 5Level of Clinical Guidance - C (Level of Evidence - 5)

• Evaluation of the efficacy of antitumor therapy using computed tomography and/or magnetic resonance imaging with intravenous bolus contrast enhancement is recommended to be carried out 2–3 months after completion of therapy.

LoR CLevel of Recommendation - C (Level of Evidence - 5)

Comment: performing Positron Emission Tomography combined with Computed Tomography using tumorotropic radiopharmaceuticals to assess treatment efficacy should be considered only if baseline data are available. Tumor response evaluation should be performed according to RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 (Appendix G) and their modifications (iRECIST, mRECIST, PERCIST).

2.5 Other Procedures

Pathological and genetic diagnostics

Comment: It is advisable to refer patients with a suspected tumor of unknown primary site immediately after performing routine morphological examination of the biopsy (surgical) material of the affected organ for telemedical and/or in-person consultation to a 4th category pathological department (Reference Center) [1. ORDER No. 179n dated March 24, 2016, On Approval of the Rules for Conducting Pathological and Anatomical Examinations (as amended on March 25, 2019 – ORDER No. 158n dated March 25, 2019 "On Amendments to the Rules for Conducting Pathological and Anatomical Examinations", approved by Order of the Ministry of Health of the Russian Federation No. 179n dated March 24, 2016); 2. Order of the Ministry of Health of the Russian Federation No. 965n dated November 30, 2017, "On Approval of the Procedure for Organizing and Providing Medical Care Using Telemedicine Technologies" (registered by the Ministry of Justice of the Russian Federation on January 9, 2018, registration No. 49577) [55].

• To improve the accuracy of determining the primary source of the tumor, it is recommended that patients with a suspected tumor of unknown primary site undergo pathological examination of the biopsy (surgical) material of the affected organ using immunohistochemical (IHC) methods (A08.30.013 Pathological examination of biopsy (surgical) material using immunohistochemical methods) in fourth-category pathology departments and/or in departments whose staff have undergone appropriate training [56].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

Comments: In accordance with the letter of the Russian Ministry of Health dated June 23, 2023, No. 17-2/I/2-11241, medical organizations of the constituent entities of the Russian Federation are recommended to undergo external quality control of pathological examinations of biopsy (surgical) material using immunohistochemical methods [56].

The completeness of the antibody panel in the IHC assay is determined taking into account the morphological picture on hematoxylin and eosin staining, clinical and anamnestical data (localization of the lesion, assumptions about the primary tumor location), results of imaging studies (CT, MRI), as well as the availability of the required set of diagnostic antibodies in the morphology laboratory.

In cases of an extremely small volume of diagnostic material, immunocytochemical (ICC) staining of biological material with a minimal panel of tissue- and organ-specific antibodies can be used – Immunocytochemical examination of biological material (A08.30.004). IHC and ICC studies should preferably be performed in medical research centers with a highly qualified pathology service and an expanded panel of diagnostic antibodies.

The initial broad-spectrum panel to determine tumor histogenesis may include: Cytokeratins (CK7, CK20): CK7+/CK20-: lung, breast, ovarian, endometrial cancer; CK7-/CK20+: colorectal and Merkel cell carcinoma. Vimentin: identifies mesenchymal tumors, melanoma, and some carcinomas. CD45 (lymphomas). S100: primarily used for melanomas and neurogenic tumors [13-17].

Existing IHC markers, in addition to the initial panel and with appropriate clinical interpretation, allow in most cases to diagnose the organ origin of the following types of metastatic cancer [13-17]:

• squamous cell carcinoma (determining the organ origin of the tumor is limited to primary localization in the skin, thymus, and HPV-associated areas (head and neck, anogenital area) – p40, p63, p16);

• adenocarcinomas (determining the organ origin of the tumor is limited to primary localization in the lung (TTF1, Napsin A), breast (GATA3*, GCDFP-15, and mammaglobin), female reproductive system (PAX8, ER, PR, WT1, p53), pancreatobiliary zone (PDX1*, CK19), small and large intestine (CDX2, CK20, SATB2*), urinary system (GATA3*, PAX8), serous membranes (WT1, HBME-1), thyroid gland (TTF1, Galectin-3), prostate gland (p504S/AMACR, Androgen receptor));

• renal cell carcinoma (PAX8);

• hepatocellular carcinoma (Arginase-1*, Hep-Par-1);

• germ cell tumors (PLAP, OCT4, CD30, SALL4*);

• soft tissue sarcomas Desmin, aSMA, Myogenin, MyoD1, CD99, CD34, CD117, DOG1, SOX10*, ERG*.

• neuroendocrine tumors (determining the organ origin of the tumor is limited to primary localization in the lung, pancreas, gastrointestinal tract, thyroid gland – Chromogranin A, Synaptophysin, INSM-1*, and CD56 in combination with additional markers).

Existing IHC markers in 20-100% of cases do not allow accurate differentiation of the organ origin of the following types of metastatic cancer [4, 5]:

• esophageal adenocarcinoma;

• gastric adenocarcinoma;

• gastrointestinal adenocarcinomas proximal to the left colon;

• TTF-1-negative lung adenocarcinoma;

• small-cell and large-cell neuroendocrine carcinomas (except for Merkel cell carcinoma and small-cell cervical carcinoma).

In cases where the primary site cannot be established, but only the lines of tumor cell differentiation, a panel of markers can be used to select therapy (Her2, PD-L1, MLH1, PMS2, MSH2, MSH6, BRAF, ALK, pan-TRK) [57-61].

• If there is no objective possibility to accurately judge the histological type of the tumor, its line of differentiation, and/or organ origin after the IHC study, it is recommended to stop the diagnostic phase of the IHC study in order to preserve the biopsy (surgical) material for subsequent evaluation of drug sensitivity markers using IHC, PCR, FISH, NGS methods [57-61].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

Comments: * - antibodies for immunohistochemical studies without a registration certificate.

• Patients with a suspected tumor of unknown primary site are recommended to undergo molecular genetic testing for mutations in biopsy (surgical) and/or cytological material and/or blood plasma to identify the primary tumor focus, refine treatment tactics, and identify mutations determining tumor sensitivity to targeted drugs [57-61].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

Comments: New molecular methods can identify the tissue of origin and be used to select systemic agnostic therapy for various malignant neoplasms with specific molecular anomalies. Targetable driver mutations or gene rearrangements can be identified using various molecular methods—gene expression profiling at the mRNA level and microRNA expression using microarrays or reverse transcription-polymerase chain reaction (RT-PCR), as well as DNA methylation testing using methylation-specific PCR (MS-PCR). In addition, PCR, RT-PCR, sequencing, including next-generation sequencing (NGS), and fluorescence in situ hybridization (FISH) can be used to determine the presence of driver mutations and gene rearrangements in the tumor or circulating cell-free DNA (cfDNA) [57-61].

Liquid biopsy provides a molecular profile of all tumor foci, facilitating the identification of the organ where the cancer developed. However, a limitation of liquid biopsy is its insufficient sensitivity, especially in patients with oligometastatic disease. In these cases, the amount of circulating tumor DNA (ctDNA) and mRNA may be too low for reliable genetic testing [58,59].

Molecular tests for cancer of unknown primary (CUP) are performed using biopsy material from the metastatic tumor or via liquid biopsy (usually involving peripheral blood) [58,59].

The most common genetic rearrangements are KRAS gene mutations, which occur in approximately 50% of colorectal cancer cases and 30% of non-small cell lung cancer, pancreatic cancer, and thyroid cancer [60,61].

Examples of such alterations include NTRK1, NTRK2, and NTRK3 gene rearrangements, which can be associated with various cancer types, including NSCLC, colon cancer, and rectal cancer. These abnormalities are observed in more than 75% of secretory breast carcinomas and mammary analogue secretory carcinomas of the salivary glands. NTRK gene rearrangements are also relatively common in gastrointestinal stromal tumors, thyroid cancer, and certain rare pediatric and adolescent malignancies such as fibrosarcoma (>75%) [60,61].

EGFR gene mutations in exons 18–21, detected in cfDNA or tumor cells from metastatic sites, confirm the diagnosis of NSCLC with the same probability as pathomorphological examination [60,61].

In one of the largest studies included in the meta-analysis, hot-spot sequencing of more than 70 genes in cfDNA was performed in 442 patients with CUP; genomic rearrangements were detected in 66% of patients, with the most frequently affected genes being TP53 (37%), KRAS (19%), PIK3CA (15%), BRAF (7.5%), and MYC (7.5%) [60,61].

• In adenocarcinoma: molecular genetic testing for mutations in the EGFR (molecular genetic testing for mutations in the EGFR gene in biopsy/surgical material, molecular genetic testing for mutations in the EGFR gene in blood by PCR), KRAS (molecular genetic testing for mutations in the KRAS gene in biopsy/surgical material), NRAS (molecular genetic testing for mutations in the NRAS gene in biopsy/surgical material), BRAF (molecular genetic testing for mutations in the BRAF gene in biopsy/surgical material), PIK3CA, FGFR, IDH1,2 (molecular genetic testing for mutations in the IDH1 gene in biopsy/surgical material, molecular genetic testing for mutations in the IDH2 gene in biopsy/surgical material), RET (molecular genetic testing for mutations in the RET gene in blood, molecular genetic testing for mutations in the RET gene in biopsy/surgical material), MET, c-KIT (molecular genetic testing for mutations in the c-KIT gene in biopsy/surgical material), PDGFRA (molecular genetic testing for mutations in the PDGFRA gene) genes in biopsy or surgical material, and molecular genetic testing for ALK (molecular genetic testing for ALK gene translocations), NTRK, ROS1 (molecular genetic testing for ROS1 gene translocations), and RET translocations; molecular genetic testing for BRCA1/2 mutations in blood or tumor tissue using PCR and/or NGS (molecular genetic testing for mutations in the BRCA1 and BRCA2 genes in blood, molecular genetic testing for mutations in the BRCA1 gene in biopsy/surgical material, molecular genetic testing for mutations in the BRCA2 gene in biopsy/surgical material).

• In case of a family history of cancer: hereditary mutation testing following a geneticist's consultation.

• Regardless of the histological tumor type, determination of microsatellite DNA repeats in biopsy (surgical) material by PCRand/or NGS; To assess the feasibility immunotherapy (with pembrolizumab**): determination microsatellite DNA repeats (MSI) using molecular genetic methods (PCR method with probes for BAT25, BAT26, NR21, NR24, Mono27 or for BAT25, BAT26, Di5S346, Di2S123, Di 17S250, in which differences in size are detected in ≥2 loci) or IHC method (with antibodies to gene proteins MSH2, MSH6, PMS2, MLH1 upon expression of at least of one protein - determination of mutations in genes MLH1, MSH2, MSH6, PMS2 by immunohistochemistry).

• In tumors of mesenchymal origin: translocations (EWSR1 (molecular genetic testing for mutations in the EWSR1 gene in biopsy/surgical material, determination of EWSR1 gene translocation in biopsy/surgical material by fluorescence in situ hybridization (FISH)), PAX3-FOXO1, PAX7-FOXO1, SYT (determination of SYT gene translocation in biopsy/surgical material by fluorescence in situ hybridization (FISH)), ALK, ROS1, NTRK, etc.), specific to various types of sarcomas.

The feasibility, range, and sequence of molecular genetic tests in each individual case should preferably be discussed with specialists in clinical and molecular genetics who will perform the analysis. Pathoanatomical examination of biopsy (surgical) material using immunohistochemical methods is the basis for establishing the diagnosis of a malignant tumor and selecting the further diagnostic algorithm. Molecular genetic testing, such as comprehensive genomic profiling based on high-throughput next-generation sequencing (NGS), is adjunctive and can assist in choosing management strategies and personalizing patient treatment.

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

Treatment tactics are determined primarily based on the patient's general condition, localization of metastases, extent of the tumor process, morphological structure of the metastatic tumor, and presumed localization of the primary focus.

Surgical treatment in patients with cancer of unknown primary (CUP) is not radical and may be used for isolated involvement of a resectable lymph node group and, in some cases, isolated organ involvement; lymphadenectomy or metastasectomy with organ resection is possible. Surgical intervention may also be performed for palliative and/or therapeutic purposes and/or for morphological verification.

Radiation therapy, when surgery is not feasible, may be indicated for therapeutic and/or palliative purposes in cases of isolated lymph node involvement or tumor location amenable to radiotherapy.

The mainstay of treatment for metastatic cancer of unknown primary is systemic medical therapy.

Therapy is planned individually, taking into account clinical and morphological data. Certain subtypes are distinguished that are more sensitive to medical treatment and resemble specific primary sites of malignant tumors, but differ by a significantly worse prognosis and therapeutic sensitivity. If mutations determining the efficacy of targeted therapy are identified in the tumor tissue, appropriate drugs may be used. Molecular genetic testing data on sensitivity to antineoplastic agents can be used to select a treatment regimen. In addition, comprehensive genomic profiling data based on high-throughput next-generation sequencing may be additionally used to prescribe personalized therapy. The efficacy of the treatment is evaluated using one of the response evaluation systems at a frequency of at least once every 6–12 weeks of treatment, depending on the clinical situation. Evaluation of therapy should rely on the same diagnostic imaging methods and objective measurements as those used before the start of treatment, with a mandatory assessment of the clinical manifestations of the disease. A change in the treatment regimen is made upon disease progression proven by objective methods (CT, MRI, PET-CT). The preferred system for evaluating treatment efficacy is the RECIST 1.1 system or its modification for immunotherapy (iRECIST) [67]. The treatment regimen is modified when signs of toxicity appear that prevent the planned treatment from being administered in full. After completion of treatment, the follow-up frequency is determined by the dispensary observation schedule.

Treatment of patients with adenocarcinoma or poorly differentiated carcinoma with isolated involvement of the cervical lymph nodes (including the supraclavicular region)

Comments: The disease course in such patients corresponds to that of corresponding head and neck tumors.

Treatment of patients with adenocarcinoma or poorly differentiated carcinoma with isolated involvement of the axillary lymph nodes

• In female patients, it is recommended to administer treatment in accordance with the standards developed for breast cancer [19].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• In male patients, it is recommended to perform axillary lymphadenectomy; radiation therapy may be administered if indicated [20].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Treatment of patients with adenocarcinoma or poorly differentiated carcinoma with predominant involvement of axial lymph nodes (mediastinal in patients under 50 years of age, retroperitoneal)

Table 1. Possible chemotherapy regimens for poorly differentiated CUMPs with predominant involvement of axial lymph nodes [30, 50].

¹The chemotherapy regimen is associated with a high risk (>20%) of febrile neutropenia, therefore primary G-CSF prophylaxis is required (for adult patients: empegfilgrastim** 7.5 mg s.c. 24–72 hours after the end of chemotherapy or filgrastim** at a dose of 0.5 million IU (5 mcg)/kg daily subcutaneously according to the protocols of clinical guidelines for the prevention of febrile neutropenia [31,32]).

²Alternative options for administering these treatment regimens are possible.

³It is possible to replace #cisplatin** with #carboplatin AUC-6** with a dose reduction of etoposide** to 100 mg/m2 on days 1, 2, and 3.

⁴For the CUMP subtype whose clinical course is similar to germ cell tumors, replacing cisplatin with carboplatin is undesirable.

Comments: for the EP and GP regimens, other regimen modifications are also possible [29], which can be used in the treatment of this category of patients.

Treatment of patients over 50 years of age with adenocarcinoma or poorly differentiated carcinoma, as well as patients with squamous cell carcinoma with predominant mediastinal involvement

Treatment of patients with poorly differentiated neuroendocrine carcinoma of unknown primary site

Comment: The disease course in such patients corresponds to small cell lung cancer and treatment is carried out in accordance with the recommendations developed for neuroendocrine tumors with high proliferative activity or for small cell lung cancer. Platinum derivatives-containing regimens form the basis of therapy.

Treatment of patients with well-differentiated neuroendocrine tumors with low proliferative activity

Comment: The disease course in such patients corresponds to that of well-differentiated gastrointestinal neuroendocrine tumors.

Peritoneal carcinomatosis in female patients

Comment: The disease course in female patients corresponds to ovarian cancer. Patient management is carried out based on the recommendations for this disease, taking into account the stage of the process.

Squamous cell carcinoma involving head and neck lymph nodes

Comment: The disease course corresponds to that of squamous cell carcinoma of the aforementioned locations and treatment is carried out according to the standards developed for this disease.

Treatment of male patients with adenocarcinoma of unknown primary site and osteosclerotic bone metastases and/or elevated PSA

Comment: The course of this type of CUMP corresponds to prostate cancer and treatment is carried out according to the standards adopted for this disease.

Patients with melanoma or sarcoma of unknown primary site

Pediatric patients with CUMP of mesenchymal or neuroectodermal origin and melanoma

Treatment of CUMP patients, including pediatric patients, not belonging to the above-listed groups

Comment: Due to the low sensitivity of such tumors to therapy, preference is given to low-toxicity regimens. The choice of drugs is based on the assumption that the primary source of CUMP is most frequently located in the gastrointestinal tract and lungs. The use of combination chemotherapy (Tables 2, 3) is justified only in patients in satisfactory condition with an aggressively progressing disease. In patients with metastatic bone lesions, the use of bisphosphonates or denosumab** is indicated for the prevention of bone-related complications [19, 35, 36, 39].

In multiple bone metastases (3 or more foci) accompanied by pain syndrome, confirmed by whole-body bone scintigraphy with tumor-tropic radiopharmaceuticals along with X-ray control of suspicious areas, or verified by whole-body single-photon emission computed tomography (SPECT) of bones, bone X-ray, or magnetic resonance imaging (MRI) of bone tissue (one region), experts recommend considering the feasibility and necessity of radionuclide therapy with osteotropic radiopharmaceuticals [39].

For CUP patients with bone marrow metastases confirmed by cytological examination of a bone marrow smear (myelogram) and an ECOG score of no more than 2 (Appendix G), consider administering systemic antineoplastic drug therapy (monochemotherapy with #paclitaxel** or anthracyclines [L01DB: Anthracyclines and related substances] or pyrimidine analogues [fluoropyrimidines], weekly regimens of #paclitaxel** or anthracyclines, hormone therapy, targeted therapy) in an inpatient setting providing the necessary supportive care. For patients with an ECOG score of 3 or higher (Appendix G), palliative care at home. The decision is made by a multidisciplinary tumor board.

Table 2. Possible treatment regimens for patients with carcinoma of unknown primary [30, 50].

¹The chemotherapy regimen is associated with a high risk (>20%) of febrile neutropenia, therefore primary G-CSF prophylaxis is required for adults (empegfilgrastim** 7.5 mg subcutaneously 24–72 hours after completion of chemotherapy, or filgrastim** at a dose of 0.5 million IU/kg/day daily subcutaneously in accordance with clinical practice guidelines for the prevention of febrile neutropenia [80,81]).

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

Comments on the treatment of patients with carcinoma of unknown primary:

²Alternative options for administering cisplatin** in this regimen are possible, including dividing the dose equally between days 1 and 8.

^4.Administration of colony-stimulating factor from days 9 to 15.

⁵Bolus administration of fluorouracil** may be omitted.

⁶Only in the presence of MSI-H in tumor tissue, determined by the methods described above. In the second or subsequent lines of therapy.

⁷In the presence of PD-L TPS ³ 1% in tumor tissue, determined by the methods described above. In the second or subsequent lines of therapy.

⁸ This regimen is indicated for patients with an ECOG performance status of 0–1, age under 65 years, and a suspected primary tumor location in the gastrointestinal tract.

Other modifications of the GP regimen may be used [30]; for patients with unresectable or metastatic solid tumors harboring a BRAF V600E mutation who have progressed after prior treatment and lack effective alternative treatment options, the combination of #dabrafenib** 150 mg twice daily + #trametinib 2 mg once daily every 4 weeks may be considered in the presence of the BRAF V600E mutation [63].

Only in metastatic solid tumors with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion when effective alternative therapies are absent, the following may be considered: #entrectinib 600 mg orally once daily every 4 weeks or #larotrectinib (for adults) 100 mg orally twice daily every 4 weeks [64,83].

In the presence of TMB-H (≥10 mut/Mb): #pembrolizumab** 200 mg IV once every 3 weeks [65].

In the presence of TMB (≥7.75 mut/Mb): #nivolumab** 240 mg IV once every 2 weeks [66].

In the presence of HER2 overexpression (+++) in tumor tissue determined by the methods described above, #trastuzumab deruxtecan 5.4 mg IV once every 21 days is indicated in the second or subsequent lines of therapy [67].

Table 3. Possible treatment regimens for patients with squamous cell carcinoma of unknown primary [30, 50].

¹Consider the administration of G-CSF in accordance with clinical practice guidelines for the prevention of febrile neutropenia [31, 32].

¹The chemotherapy regimen is associated with a high risk (>20%) of febrile neutropenia, therefore primary G-CSF prophylaxis is required (empegfilgrastim** 7.5 mg SC 24–72 hours after the end of chemotherapy or filgrastim** at a dose of 0.5 million IU/kg per day daily subcutaneously in accordance with the clinical practice guidelines for the prevention of febrile neutropenia [80,81])

Comments for the treatment of patients with squamous cell carcinoma of unknown primary:

³It is possible to omit the bolus administration of fluorouracil**.

⁵Only in the presence of MSI-H in the tumor tissue, determined by the methods described above. In the second or subsequent lines of therapy.

⁶Only in the presence of PD-L TPS ³ 1% in the tumor tissue, determined by the methods described above. In the second or subsequent lines of therapy.

⁷It is possible to consider prescribing these regimens without calcium folinate**.

Other modifications of the GP regimen may be used [30]; for patients with unresectable or metastatic solid tumors harboring a BRAF V600E mutation who have progressed after prior treatment and lack effective alternative treatment options, the combination of #dabrafenib** 150 mg twice daily + #trametinib 2 mg once daily every 4 weeks may be considered in the presence of the BRAF V600E mutation [63].

Only in metastatic solid tumors with neurotrophic tyrosine receptor kinase (NTRK) gene fusion when effective alternative treatments are lacking, it is possible to consider: #entrectinib 600 mg orally once daily every 4 weeks or #larotrectinib (for adults) 100 mg orally twice daily every 4 weeks [64,83]

In the presence of TMB-H (≥10 mut/Mb), #pembrolizumab 200 mg IV once every 3 weeks [65].

In the presence of TMB (≥7.75 mut/Mb), #nivolumab 240 mg IV once every 2 weeks [66].

Supportive care

• For chemotherapy regimens associated with a risk of febrile neutropenia (FN) greater than 20% in patients with cancer of unknown primary, it is recommended to use filgrastim**, empegfilgrastim**, pegfilgrastim, or other colony-stimulating factors for the primary prophylaxis of febrile neutropenia (FN) [31, 32].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: Primary and secondary prophylaxis is carried out according to existing guidelines [31, 32]. Treatment of FN using systemic anti-infective agents and hematopoietic stimulants (L03 immunostimulants) in combinations is carried out according to existing guidelines [31, 32].

• For patients with cancer of unknown primary, nausea and vomiting prophylaxis during chemotherapy, radiation therapy, and/or chemoradiotherapy is recommended to be carried out according to data on the incidence of nausea and vomiting of the antineoplastic agent or radiation field [33, 34, 35].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• The use of bone-modifying agents: bisphosphonates and denosumab**, as well as calcium and cholecalciferol* preparations, is recommended for patients with metastatic bone lesions (zoledronic acid** 4 mg IV infusion every 28 days or every 3 months, or other bisphosphonates, denosumab** 120 mg SC every 28 days) for the prevention of complications, as well as for the prevention of bone mineral density loss (zoledronic acid** 4 mg IV infusion every 6 months or other bisphosphonates, denosumab** 60 mg SC every 6 months) when using gonadotropin-releasing hormone analogues (luteinizing hormone-releasing hormone (LHRH) antagonists), aromatase inhibitors, radiation or surgical castration (A16.21.010.001, orchofuniculectomy) in accordance with existing guidelines [36, 39].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• For the treatment of complications associated with antineoplastic monoclonal antibody therapy (nivolumab**, pembrolizumab**), it is recommended to use glucocorticoids, #infliximab** 5 mg/kg at weeks 0, 2, 6, followed by 5 mg/kg every 8 weeks, and additionally follow clinical guideline protocols or clinical guidelines for managing these complications [40, 41, 42, 43].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• Treatment and prevention of gastrointestinal (diarrhea and constipation), cardiovascular, hepatic, renal, dermatological, and thromboembolic complications in patients with cancer of unknown primary site, as well as extravasation, are recommended to be carried out in accordance with existing guidelines [44].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: it is necessary to consider modifying/adjusting the treatment regimen and/or prescribing supportive (concomitant) therapy if other complications > grade 2 develop.

3.7 Pain management

3.14 Nutritional therapy

Prevention and treatment of nutritional deficiency in patients with cancer of unknown primary site must be carried out based on supportive care guideline protocols including enteral nutrition for sipping or oral intake, as well as parenteral nutrition and intravenous preparations containing vitamins and minerals [46-47].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Currently, there are no clinical studies involving patients with cancer of unknown primary site for most types of medical rehabilitation. These recommendations are based on the fact that numerous studies, including meta-analyses (Steffens, D et al., 2018, and others) and systematic reviews (Nicole L. Stout et al., 2017, R. Segal et al., 2017, and others), have proven that various types of medical rehabilitation significantly accelerate functional recovery, reduce hospital stay duration after surgery, and lower the incidence of complications and mortality rates in patients with other malignant neoplasms.

Comments: rehabilitation may be considered for patients with cancer of unknown primary site, guided by rehabilitation principles depending on the suspected location of the primary tumor and the surgical, antineoplastic drug, and/or radiation therapy performed. These principles are outlined in the relevant sections of the RASS clinical guidelines [82].

5. Prevention and Dispensary Observation

• During the first 1–2 years after completion of treatment, it is recommended to evaluate the patient every 1–3 months, although there are no conclusive guidelines on the necessary interval for follow-up examinations after treatment [29].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

- Medical history and physical examination.

- According to clinical indications: complete blood count (CBC) with differential and general biochemical blood test; contrast-enhanced computed tomography (CT) of the chest organs with intravenous bolus injection, contrast-enhanced computed tomography (CT) of the abdominal and retroperitoneal organs with intravenous bolus injection; contrast-enhanced magnetic resonance imaging (MRI) of the pelvic organs; comprehensive ultrasound examination of the abdominal organs, comprehensive ultrasound examination of the pelvic organs (transvaginal and transabdominal), ultrasound examination of the prostate gland, ultrasound examination of lymph nodes (one anatomical zone) of the cervical-supraclavicular and axillary regions; positron emission tomography combined with computed tomography (PET-CT) using tumor-tropic radiopharmaceuticals with contrast enhancement.

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

Comment: in patients with solitary or oligometastatic cancer of unknown primary site, follow-up monitoring should be performed at intervals of 3–6 months for 2 years, and then at intervals of 6–12 months for 3–5 years.

6. Organization of Medical Care

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

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

2. in accordance with the procedure for providing care in the profile "oncology", mandatory for execution on the territory of 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 an oncological disease is suspected or detected in a patient, general practitioners, district general practitioners, general family practitioners, medical specialists, and mid-level medical personnel shall refer the patient in the established 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 an outpatient oncological care center or at a primary oncological office or primary oncological department of a medical organization must be conducted no later than 5 working days from the date of issuance of the referral for consultation. 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 organize the collection of biopsy (surgical) material, as well as organize other diagnostic studies necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

In the event that it is impossible to obtain biopsy (surgical) material or perform other diagnostic examinations within the medical organization that houses the outpatient oncological care center (primary oncological office, primary oncological department), the attending physician shall refer the patient to an oncological dispensary or a medical organization providing medical care to patients with oncological diseases.

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

If an oncological disease is suspected and/or detected in a patient during the provision of emergency medical care, such patients are transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine the management tactics and the need for additional specialized anti-tumor treatment methods.

An oncologist at an outpatient oncological care center (primary oncological office, primary oncological department) refers patients to an oncological dispensary or to medical organizations providing medical care to patients with oncological diseases for diagnosis clarification (if the oncologist at the outpatient oncological care center, primary oncological office, or primary oncological department is unable to establish a diagnosis, including the extent of the oncological process and the stage of the disease) and for the provision of specialized, including high-tech, medical care.

The timeframe for initiating the provision of specialized, excluding high-tech, medical care to patients with oncological diseases in a medical organization providing medical care to patients with oncological diseases must not exceed 14 calendar days from the date of histological verification of the malignant neoplasm or 14 calendar days from the date of establishing a preliminary diagnosis of a malignant neoplasm (in the absence of medical indications for performing pathomorphological examinations in an outpatient setting).

Specialized, including high-tech, medical care is provided by oncologists and radiation therapists in an oncological dispensary or in medical organizations providing medical care to patients with oncological diseases that have a license, the necessary material and technical base, and certified specialists, in inpatient and day-care settings, and includes the prevention, diagnosis, and treatment of oncological diseases 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 oncological diseases, the tactics of medical examination and treatment are determined by a concilium of oncologists and radiation therapists, with the involvement of other medical specialists if necessary. The decision of the concilium of physicians is formalized in a protocol, signed by the participating physicians, and entered into the patient's medical documentation.

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

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

1. presence of complications of the oncological disease requiring the provision of specialized medical care in an emergency and urgent form;

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

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

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

2. the presence of indications for specialized anti-tumor treatment (surgical intervention, radiation therapy—including contact, external beam, and other types of radiation therapy—drug therapy, etc.) requiring monitoring in an inpatient or day-inpatient setting.

3. pediatric age.

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 established by the concilium of the medical organization providing oncological care, in the absence of complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting;

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

7. Additional Information

No additional information available.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Module on the diagnosis and treatment of ONPL in adults:

1. Anton V. Snegovoy, MD, PhD, Head of the Department of Drug Treatment of Tumors, Research Institute of Urology and Interventional Radiology – branch of the National Medical Research Radiological Center of the Russian Ministry of Health. Professor at the Department of Oncology of the Faculty of Additional Professional Education, Russian University of Medicine of the Russian Ministry of Health.

2. Alexey V. Novik, PhD, Senior Researcher at the Research Department of Oncoimmunology, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Associate Professor at the Saint Petersburg Pediatric Medical Academy.

3. Sergey L. Gutorov, MD, PhD, Leading Researcher at the Department of Chemotherapy and Combined Treatment of Malignant Tumors, N.N. Blokhin Russian Cancer Research Center of the Russian Ministry of Health.

4. Inessa B. Kononenko, PhD, Head of the Day Hospital for Drug Treatment of Tumors, Research Institute of Urology and Interventional Radiology – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

5. Vladimir Yu. Selchuk, MD, DSc, Professor, Head of the Department of Oncology, Faculty of Continuing Medical Education, Russian University of Medicine of the Russian Ministry of Health.

6. Eduard K. Vozny, MD, DSc, Professor, Department of Chemotherapy, City Clinical Hospital named after D.D. Pletnev of the Moscow Healthcare Department.

7. Nikolay A. Kozlov, PhD, Leading Researcher, Department of Pathology, National Medical Research Center for Oncology named after N.N. Blokhin of the Russian Ministry of Health.

8. Dmitry V. Kalinin, PhD, Head of the Department of Pathology, National Medical Research Center of Surgery named after A.V. Vishnevsky of the Russian Ministry of Health.

9. Lyudmila N. Lyubchenko, MD, DSc, Professor, Head of the Department of Molecular Genetics and Cellular Technologies, National Medical Research Center for Radiology of the Russian Ministry of Health.

10. Tatev A. Aghababyan, PhD, Head of the Department of Diagnostic Radiology, Medical Radiological Research Center named after A.F. Tsyb – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health, Obninsk.

11. Natalia A. Rubtsova, MD, DSc, Head of the Department of Diagnostic Radiology, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health. Chief Freelance Specialist in Diagnostic Radiology and Instrumental Diagnostics of the Russian Ministry of Health in the Central Federal District of the Russian Federation.

12. Malika M. Khodjibekova, MD, DSc, Radiologist, Department of Radionuclide Diagnostics, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

Section on Diagnosis and Treatment of CUP in Children:

1. Kachanov Denis Yu., MD, DSc, 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.

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

Medical Care Organization Section

1. Nevolskikh A.A., MD, DSc, Deputy Director for Medical Work, Medical Radiological Research Center named after A.F. Tsyb – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

2. Ivanov S.A., Professor of the Russian Academy of Sciences, MD, DSc, Director of the Medical Radiological Research Center named after A.F. Tsyb – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

3. Khaylova Zh.V., PhD, Deputy Director for Organizational and Methodological Work, Medical Radiological Research Center named after A.F. Tsyb – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

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

5. Litvinov D.V., MD, DSc, Deputy General Director for Medical Work – Chief Physician, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Oncologists.

2. Pediatric oncologists.

3. Surgeons.

4. Pediatric surgeons.

5. Radiologists.

6. Medical geneticists.

7. Medical students, residents, and postgraduate students.

• Methods used for evidence collection/selection: search in electronic databases; analysis of current scientific developments on the problem in the Russian Federation (RF) and abroad; synthesis of practical experience of Russian and foreign specialists.

Table S1. Scale for assessing Levels of Evidence (LoE) for diagnostic methods (diagnostic interventions).

Table A2. Levels of Evidence (LoE) grading scale for methods of prevention, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table S3. Scale for assessing Grades of Recommendation (GoR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, rehabilitation interventions).

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 recommendation validation method. The preliminary version of these guidelines was reviewed by independent experts who were asked to comment primarily on how comprehensible the interpretation of the evidence underlying the recommendations is.

Comments were received from primary care pediatric oncologists regarding the clarity of the presentation of the recommendations and their assessment of the importance of the recommendations as a 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 made to the recommendations were recorded. If no changes were made, the reasons for refusing to make changes were recorded.

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

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

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. 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

1. Federal Law No. 323-FZ of November 21, 2011 "On the Fundamentals of Protecting Citizens' Health in the Russian Federation".

2. Order of the Russian Ministry of Health No. 116n dated February 19, 2021 (as amended on January 24, 2022) "On Approval of the Procedure for Providing Medical Care to Adult Patients with Oncological Diseases" (Registered with the Ministry of Justice of Russia on April 1, 2021, No. 62964)

3. Order of the Russian Ministry of Health No. 804n dated October 13, 2017 (as amended on April 16, 2019) "On Approval of the Nomenclature of Medical Services" (Registered with the Ministry of Justice of Russia on November 7, 2017, No. 48808)

4. Letter of the Federal Compulsory Medical Insurance Fund No. 5071/26-2/i dated April 23, 2019. http://www.ffoms.ru/documents/the-orders-oms/.

Appendix B. Physician Action Algorithms

Given the absence of primary sites, the physician's course of action is individual in nature.

Appendix C. Patient Information

Taking into account the absence of primary sites, recommendations are given to the patient depending on the treatment algorithm chosen by the physician and are individual in nature.

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

Russian title: WHO Patient Performance Status Scale/ECOG

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

Source (official website of developers, publication with validation): https://ecog-acrin.org/resources/ecog-performance-status

Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982, 5(6):649-655

Type: rating scale

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

Contents:

Key (interpretation): provided within the scale itself

Criteria for evaluating response in solid tumors according to RECIST 1.1 (Response Evaluation Criteria in Solid Tumors)

Russian title: Criteria for evaluating treatment efficacy in solid tumors

Original title: Response Evaluation Criteria In Solid Tumours (version 1.1)

Source: Eisenhauer E. A., Therasse P., Bogaerts J., Schwartz L. H., Sargent D., Ford R. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European Journal of Cancer. 2009. 45 (2): 228–247. Epub 23 December 2008

Purpose: evaluation of response to anti-tumor treatment

Content (template) and keys (interpretation):