Neuroendocrine tumors: clinical guidelines

List of Abbreviations

AH – arterial hypertension

ASBS – arterial-stimulated blood sampling

SSA – somatostatin and its analogues

ACTH – adrenocorticotropic hormone

NOS – not otherwise specified

IV – intravenous

VIP – vasoactive intestinal peptide

WHO – World Health Organization

GI – gastrointestinal tract

IHC – immunohistochemical

CT – computed tomography

MRI – magnetic resonance imaging

MTC – medullary thyroid carcinoma

MEN – multiple endocrine neoplasia

NSE – neuron-specific enolase

NET – neuroendocrine tumors

NEC – neuroendocrine carcinoma

SPECT – single-photon emission computed tomography

PGL – paraganglioma

P – pancreas

PP – pancreatic polypeptide

PTH – parathyroid hormone

PRRT – peptide receptor radionuclide therapy

PET – positron emission tomography

PET-CT – positron emission tomography combined with computed tomography

RNT – radionuclide therapy

RP – radiopharmaceutical

SRS – somatostatin receptor scintigraphy,

US – ultrasound examination

PCC – pheochromocytoma

CgA – chromogranin A

CT – chemotherapy

5-HIAA – 5-hydroxyindoleacetic acid

ENETS (European Neuroendocrine Tumor Society) – European Neuroendocrine Tumor Society

¹⁸F-FDG – fludeoxyglucose [18F]

¹⁸F-L-DOPA – ¹⁸F-fluoro-L-3,4-dihydroxyphenylalanine

G (grade) – grade of malignancy

⁶⁸Ga-DOTATATE - 68 gallium [⁶⁸Ga]  DOTA-(Tyr3)- octreotate

⁶⁸Ga-DOTATOC - ⁶⁸Ga DOTA- (Phe1)-(Tyr3)- octreotide

⁶⁸Ga-DOTANOC - ⁶⁸Ga - DOTA-(Nal3)-octreotide

MINEN (mixed neuroendocrine-non-neuroendocrine neoplasm) – mixed neuroendocrine-non-neuroendocrine neoplasm

NEC (neuroendocrine carcinoma) – neuroendocrine carcinoma

NET (neuroendocrine tumor) – neuroendocrine tumor

NOS (not otherwise specified) – not otherwise specified

NT-proBNP – N-terminal pro-brain natriuretic peptide

SEER (Surveillance, Epidemiology, and End Results) – Surveillance, Epidemiology, and End Results

STS- Somatostatin Receptor Scintigraphy              

^99mTc- HYNIC-D-(Phe1)-(Tyr3)-octreotide

** – vital and essential drugs

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

Terms and Definitions

Neuroendocrine tumors are well-differentiated neoplasms originating from neuroendocrine cells.

Neuroendocrine carcinoma is poorly differentiated neoplasms originating from neuroendocrine cells.

Somatostatin analogues (H01CB somatostatin and analogues) are chemical compounds that are analogues of the natural hormone somatostatin.

Biotherapy – a treatment method using interferons and somatostatin analogues.

Systemic chemotherapy (CT) – a treatment method using cytotoxic drugs.

Targeted therapy – a treatment method using drugs with a molecularly targeted mechanism of action.

Immunotherapy – a treatment method using immune checkpoint inhibitors.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms originating from neuroendocrine cells of the embryonic gut, possessing biologically active properties. Neuroendocrine cells have specific secretory characteristics that lead to the development of syndromes of hyperproduction of regulatory peptides, which, in turn, can lead to the development of corresponding clinical syndromes. NETs occur in all organs containing neuroendocrine cells.

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

In some patients with NETs, the disease is associated with the presence of multiple endocrine neoplasia syndromes (MEN-1, MEN-2a, and MEN-2b), which are hereditary syndromes.

In the remaining patients, the occurrence of neuroendocrine tumors is sporadic. There is a significant increase in the incidence of NETs worldwide, possibly related to improved diagnostics.

1.3 Epidemiology of the Disease or Condition

According to the SEER (Surveillance, Epidemiology, and End Results) registry, the incidence of NETs in the USA as of January 1, 2004, was 5.25 cases per 100,000 population. There has been a significant increase in the incidence of NETs of all sites over the past 30 years. Thus, taking into account the US population, 7,350 patients with NETs should be registered annually in our country (the population of Russia in 2012 was 140 million people). According to recent data, the incidence of neuroendocrine neoplasms in Russia increased from 0.03 cases per 100,000 population in 2001 to 5.19 per 100,000 population in 2019. The incidence in the USA increased from 5.25 per 100,000 population in 2004 to 8.4 per 100,000 population in 2016 (107).

The most frequent localization (66%) of NETs is the gastrointestinal tract (GIT); the predominant location is the cecum (17.1%) and rectum (16.3%). About 30% of NETs occur in the bronchopulmonary system.

NETs are frequently diagnosed at an advanced stage. Thus, according to SEER data, 50% of patients already have locoregional or distant metastases at the time of diagnosis [1].

1.4 Features of Coding the Disease or Condition

Coding according to ICD-10 is performed in accordance with the organ origin of the tumor.

C10 Malignant neoplasms of Oropharynx

C10.0 Vallecula

C10.1 Anterior surface of epiglottis

C10.2 Lateral wall of oropharynx

C10.3 Posterior wall of oropharynx

C10.4 Branchial cleft

C10.8 Malignant neoplasm of oropharynx overlapping lesion

C10.9 Oropharynx, unspecified

World Health Organization (WHO, 2019) classification

C11 Malignant neoplasms of nasopharynx

C11.0 Superior wall of nasopharynx

C11.1 Posterior wall of nasopharynx

C11.2 Lateral wall of nasopharynx

C11.3 Anterior wall of nasopharynx

C11.8 Malignant neoplasm of nasopharynx overlapping lesion

C11.9 Nasopharynx, unspecified

World Health Organization (WHO, 2019) classification

C14 Malignant neoplasm of other and ill-defined sites in the lip, oral cavity and pharynx

C14.0 Pharynx, unspecified

C14.1 Hypopharynx

C14.2 Waldeyer ring [Waldeyer]

C14.8 Malignant neoplasm of lip, oral cavity and pharynx overlapping lesion

World Health Organization (WHO, 2019) classification

C15 Malignant neoplasms of esophagus

C15.0 Cervical part of esophagus

C15.1 Thoracic part of esophagus

C15.2 Abdominal part of esophagus

C15.3 Upper third of esophagus; proximal third of esophagus

C15.4 Middle third of esophagus

C15.5 Lower third of esophagus; distal third of esophagus

C15.8 Malignant neoplasm of esophagus overlapping lesion

C15.9 Esophagus, unspecified

World Health Organization (WHO) Classification, 2019

C16 Malignant neoplasm of stomach

C16.0 Cardia, NOS

C16.1 Fundus of stomach

C16.2 Body of stomach

C16.3 Gastric antrum

C16.4 Pylorus

C16.5 Lesser curvature of stomach, NOS

C16.6 Greater curvature of stomach, NOS

C16.8 Malignant neoplasm of stomach overlapping lesion

C16.9 Stomach, unspecified

WHO Classification, 2019

C17.0 Malignant neoplasm of duodenum

C17.1 Malignant neoplasm of jejunum

C17.2 Malignant neoplasm of ileum

C17.3 Malignant neoplasm of Meckel diverticulum [Meckel]

C17.8 Malignant neoplasm of small intestine overlapping lesion

C17.9 Malignant neoplasm of small intestine, unspecified

WHO Classification, 2019

C18.0 Malignant neoplasm of cecum

C18.1 Malignant neoplasm of appendix

C18.2 Malignant neoplasm of ascending colon

C18.3 Malignant neoplasm of hepatic flexure

C18.4 Malignant neoplasm of transverse colon

C18.5 Malignant neoplasm of splenic flexure

C18.6 Malignant neoplasm of descending colon

C18.7 Malignant neoplasm of sigmoid colon

C18.8 Malignant neoplasm of colon overlapping lesion

C18.9 Malignant neoplasm of colon, unspecified

C19 Malignant neoplasm of rectosigmoid junction

C20 Malignant neoplasm of rectum

WHO Classification, 2019

C21.0 Malignant neoplasm of anus, unspecified

C21.1 Malignant neoplasm of anal canal

C21.2 Malignant neoplasm of cloacogenic zone

C21.8 Malignant neoplasm of rectum, anus and anal canal overlapping

WHO Classification, 2019

C22 Malignant neoplasm of liver and intrahepatic bile ducts

C23 Malignant neoplasm of gallbladder

C24.0 Malignant neoplasm of extrahepatic bile duct

C24.1 Malignant neoplasm of ampulla of Vater

C24.8 Malignant neoplasm of biliary tract overlapping

C24.9 Malignant neoplasm of biliary tract, unspecified

C25.0 Malignant neoplasm of head of pancreas

C25.1 Malignant neoplasm of body of pancreas

C25.2 Malignant neoplasm of tail of pancreas

C25.3 Malignant neoplasm of pancreatic duct

C25.4 Malignant neoplasm of endocrine pancreas

C25.7 Malignant neoplasm of other parts of pancreas

C25.8 Malignant neoplasm of pancreas overlapping

C25.9 Malignant neoplasm of pancreas, unspecified

WHO Classification, 2019

C26.0 Malignant neoplasm of intestinal tract, part unspecified

C26.8 Malignant neoplasm of overlapping lesion of digestive system

C26.9 Malignant neoplasm of ill-defined sites within the digestive system

WHO Classification, 2019

See above.

C33 Malignant neoplasm of trachea

C34.0 Malignant neoplasm of main bronchus

C34.1 Malignant neoplasm of upper lobe, bronchus or lung

C34.2 Malignant neoplasm of middle lobe, bronchus or lung

C34.3 Malignant neoplasm of lower lobe, bronchus or lung

C34.8 Malignant neoplasm of bronchus or lung whose site cannot be classified into any of the above

C34.9 Malignant neoplasm of bronchus or lung, unspecified site

Classification (WHO, 2015)

C37 Malignant neoplasm of thymus

C38 Malignant neoplasm of heart, mediastinum and pleura

C39 Malignant neoplasm of other and ill-defined sites within the respiratory system and chest organs

WHO classification, 2015

C48.8 Malignant neoplasm of retroperitoneum and peritoneum, with specified sites overlapping

WHO classification, 2017

C73 Malignant neoplasm of thyroid gland

WHO classification, 2017

C50 Malignant neoplasm of breast

C50.0 Nipple and areola

C50.1 Central portion of breast

C50.2 Upper-inner quadrant of breast

C50.3 Lower-inner quadrant of breast

C50.4 Upper-outer quadrant of breast

C50.5 Lower-outer quadrant of breast

C50.6 Axillary tail of breast

C50.8 Lesion of breast with specified sites overlapping

C50.9 Malignant neoplasm of breast, unspecified

WHO classification, 2012

C44 Other malignant neoplasms of skin

C44.0 Other malignant neoplasms of skin of lip

C44.1 Other malignant neoplasms of skin of eyelid, including canthus

C44.2 Other malignant neoplasms of skin of ear and external auditory canal

C44.3 Other malignant neoplasms of skin of other and unspecified parts of face

C44.4 Other malignant neoplasms of skin of scalp and neck

C44.5 Other malignant neoplasms of skin of trunk

C44.6 Other malignant neoplasms of skin of upper limb, including shoulder

C44.7 Other malignant neoplasms of skin of lower limb, including hip

C44.8 Other malignant neoplasms of skin with specified sites overlapping

C44.9 Other malignant neoplasms of skin, site unspecified (excluding skin of penis C60.9 and skin of scrotum C63.2)

WHO classification, 2018

C51.0 Malignant neoplasm of labium majus

C51.1 Malignant neoplasm of labium minus

C51.2 Malignant neoplasm of clitoris

C51.8 Malignant neoplasm of vulva with specified sites overlapping

C51.9 Malignant neoplasm of vulva, unspecified

WHO classification, 2014

C52 Malignant neoplasm of vagina

C53.0 Malignant neoplasm of internal os of cervix uteri

C53.1 Malignant neoplasm of external os of cervix uteri

C53.8 Malignant neoplasm of cervix uteri with specified sites overlapping

C53.9 Malignant neoplasm of cervix uteri, unspecified

Classification (WHO, 2014)

C54.0 Malignant neoplasm of isthmus uteri

C54.1 Malignant neoplasm of endometrium

C54.2 Malignant neoplasm of myometrium

C54.3 Malignant neoplasm of fundus uteri

C54.8 Malignant neoplasm of corpus uteri, overlapping lesion

C54.9 Malignant neoplasm of corpus uteri, unspecified. C55 Malignant neoplasm of uterus, part unspecified WHO classification, 2014

C56 Malignant neoplasm of ovary

WHO classification, 2014

C57.0 Malignant neoplasm of fallopian tube

C57.1 Malignant neoplasm of broad ligament of uterus

C57.2 Malignant neoplasm of round ligament of uterus

C57.3 Malignant neoplasm of parametrium

C57.4 Malignant neoplasm of uterine adnexa, unspecified

C57.7 Malignant neoplasm of other specified female genital organs

C57.8 Malignant neoplasm of female genital organs, overlapping lesion

C57.9 Malignant neoplasm of female genital organ, unspecified

WHO classification, 2014

See above.

C61 Malignant neoplasm of prostate

WHO classification, 2016

WHO classification, 2016

C64 Malignant neoplasm of kidney, except renal pelvis

C65 Malignant neoplasm of renal pelvis

C66 Malignant neoplasm of ureter

C67.0 Malignant neoplasm of trigone of bladder

C67.1 Malignant neoplasm of dome of bladder

C67.2 Malignant neoplasm of lateral wall of bladder C67.3 Malignant neoplasm of anterior wall of bladder

C67.4 Malignant neoplasm of posterior wall of bladder

C67.5 Malignant neoplasm of bladder neck C67.6 Malignant neoplasm of ureteric orifice

C67.7 Malignant neoplasm of urachus. C67.8 Malignant neoplasm of bladder, overlapping lesion

C67.9 Malignant neoplasm of bladder, unspecified. C68.0 Malignant neoplasm of urethra. C68.1 Malignant neoplasm of paraurethral glands

C68.8 Malignant neoplasm of urinary organs, overlapping lesion

C68.9 Malignant neoplasm of urinary organ, unspecified

WHO classification, 2016

C74.1 Malignant neoplasm of medulla of adrenal gland

C74.9 Malignant neoplasm of adrenal gland, part unspecified

WHO classification, 2017

C75.0 Malignant neoplasm of parathyroid gland

C75.1 Malignant neoplasm of pituitary gland

C75.2 Malignant neoplasm of craniopharyngeal duct

C75.3 Malignant neoplasm of pineal gland

C75.4 Malignant neoplasm of carotid body

WHO classification, 2017

C75.5 Malignant neoplasm of aortic body and other paraganglia. WHO classification, 2017

C75.8 Malignant neoplasm of pluriglandular involvement, unspecified

C75.9 Malignant neoplasm of endocrine gland, unspecified. 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 and intrahepatic bile duct

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

C80.0 Malignant neoplasm, primary site unspecified

C80.9 Malignant neoplasm, unspecified

C97 Malignant neoplasms of independent (primary) multiple sites

1.5 Classification of the disease or condition

Classification of neuroendocrine tumors by embryogenesis (Williams and Sandler, 1963)

1. FOREGUT NETs: bronchi, stomach, pancreas, duodenum.

2. MIDGUT NETs: small intestine, cecum, appendix, ileum.

3. HINDGUT NETs: colon, rectum.

Classification of neuroendocrine tumors by grade of malignancy

Currently used histological classifications of lung, pancreatic, and gastrointestinal neuroendocrine neoplasms (NENs) differ in their approaches to determining malignancy grade.

Table 1. Classification and grading system for neuroendocrine neoplasms of the lung and thymus (WHO, 2015)

Note. HPF – high-power field (× 40) = 2 mm², at least 40 fields evaluated in areas of highest mitotic density.

Accordingly, groups G_1–2 include well-differentiated neuroendocrine neoplasms of the lung and thymus (typical and atypical carcinoids); group G₃ includes poorly differentiated neuroendocrine carcinomas (NECs): large cell neuroendocrine carcinoma and small cell carcinoma.

The treatment selection algorithm depends on tumor type and stage and is based on the European Neuroendocrine Tumor Society (ENETS) guidelines (2015).

Table 2. Classification and grading system of neuroendocrine neoplasms (NENs) of the gastrointestinal and hepatopancreatobiliary organs (WHO, 2019)

 Note. Neuroendocrine neoplasms is a term encompassing well-differentiated NETs and poorly differentiated NECs. The term MINEN refers to mixed neoplasms in which the neuroendocrine component accounts for at least 30 %. The Ki-67 proliferation index is based on the evaluation of ≥500 cells in areas of highest nuclear labeling (hot spots), and the mitotic index is based on the evaluation of mitoses in 50 high-power fields (representative field of view 0.2 mm²) in areas of highest density, expressed as a mitotic index per 10 HPFs (2 mm²). Grade is determined based on the highest value. For Ki-67 index evaluation, counting using a printed image is recommended.

Classification of neuroendocrine tumors by functional activity:

1. functioning;

2. non-functioning.

Classification of neuroendocrine tumors by primary tumor localization

In the case of specific hormone production, pancreatic neuroendocrine tumors (pNETs) are subdivided into:

1. gastrinoma – gastrin, Zollinger–Ellison syndrome;

2. insulinoma – insulin, hypoglycemia;

3. VIPoma – vasoactive intestinal peptide, diarrhea, hypokalemia, achlorhydria;

4. somatostatinoma – somatostatin, diabetes mellitus, steatorrhea, cholelithiasis;

5. glucagonoma – necrolytic migratory erythema, diabetes mellitus, cachexia;

6. calcitoninoma – calcitonin;

7. ACTHoma – ACTH production, Cushing's syndrome.

There are also other very rare hormone-producing tumors.

Multiple endocrine neoplasia type 1 (MEN-1, Wermer syndrome):

1. hyperparathyroidism;

2. gastrinoma;

3. glucagonoma, insulinoma;

4. VIPoma, pancreatic polypeptide-secreting tumor, somatostatinoma, non-functioning tumors;

5. pituitary tumors;

6. prolactinoma;

7. Cushing's syndrome;

8. acromegaly;

9. thyroid-stimulating hormone-producing adenoma;

10. non-functioning adenoma;

11. adrenal tumor;

12. bronchial and thymic carcinoid.

Wermer syndrome – a familial hereditary disorder (with a 50 % transmission rate) caused by a genetic defect located on the long arm of chromosome 11 (11q13). A mutation in the gene region on 11q13 leads to unregulated proliferation of neuroendocrine cells affecting the obligate triad of organs: the synchronous or asynchronous development of hyperplasia and/or tumors of several or all 4 parathyroid glands, endocrine tumors of the pancreas, and the anterior pituitary. Less commonly, neuroendocrine tumors of the duodenum, stomach, and even more rarely – thymus, lung, thyroid, and adrenal glands occur simultaneously. Clinical manifestations of MEN-1 syndrome are highly variable, but by the age of 40, almost all patients invariably develop symptoms of hyperparathyroidism, and clinical manifestation of the disease typically occurs in the 3rd–4th decade.

Multiple endocrine neoplasia type 2 (MEN-2, Sipple syndrome):

1. medullary thyroid carcinoma (MTC);

2. pheochromocytoma (PCC);

3. hyperparathyroidism;

4. Marfanoid habitus;

5. mucosal neuromas;

6. neuropathies;

7. Lichen planus amyloidosis.

Sipple syndrome — an autosomal dominant hereditary combination of medullary thyroid carcinoma (MTC), pheochromocytoma (PCC), and parathyroid tumors. In 1974, Sizemore et al. demonstrated that MEN-2 encompasses 2 groups of patients with PCC and MTC: MEN-2a — with parathyroid adenoma, MEN-2b — without parathyroid involvement, but with mucosal neuromas and mesodermal anomalies. The genetic basis of MEN-2 is a point mutation in the RET proto-oncogene. In 95% of patients, a point mutation is detected in the c-ret proto-oncogene (10q11), which encodes the neurotrophic factor receptor that regulates the proliferation and differentiation of neural crest-derived cells.

TNM classification of neuroendocrine tumors

For gastrointestinal and pancreatic NETs, there are 2 TNM staging systems developed by ENETS and AJCC/UICC. Tumors must be staged in accordance with the TNM classification of the organ of origin.

Lung NETs are staged by TNM as non-small cell lung cancer.

For mediastinal NETs, the classification recommended for mediastinal tumors is used.

Separate TNM classifications have been approved for NETs of the following localizations (NCCN Guidelines in Oncology, 2010):

1. stomach;

2. duodenum, ampulla of Vater, jejunum, and ileum;

3. pancreas;

4. appendix;

5. colon and rectum.

1.6 Clinical presentation of the disease or condition

The clinical presentation of NETs is diverse and depends on the localization and functional activity of the tumor.

Clinical manifestations are primarily associated with the localization of the tumor, as well as, in functioning tumors, with syndromes caused by the production of biologically active substances. Due to the variety of arising syndromes, the disease can mimic other conditions for a long time, making accurate diagnosis very difficult. Non-functioning tumors can be asymptomatic for a long time and are often an incidental finding during examinations performed for other reasons. Clinical symptoms in non-functioning NETs are nonspecific and may be caused by local tumor spread or metastatic disease.

Classic symptoms include diarrhea, flushing, skin hyperemia, and in rare cases, bronchospasm. Intestinal colic, telangiectasia, edema, cyanosis, joint involvement, myalgia, and myopathy are much less common. To varying degrees, sweating, skin edema, urticaria, pruritus, dry skin and mucous membranes, lacrimation, headache, migraines, paresthesia, tearfulness, depression, insomnia, hyperexcitability, and a "fear of impending death" may also occur. Diarrhea is the most frequent symptom and, if left untreated, becomes constant, accompanied by abdominal pain, sometimes nausea or vomiting. The severity of diarrhea varies from several episodes to 30 or more times per day. Chronic fluid loss manifests as symptoms of dehydration and deterioration of general condition, which significantly impacts patients' quality of life and sometimes leads to complete exhaustion and disability. Flushes are also one of the main symptoms of functioning NETs. A typical flush is of the erythematous type; in classic carcinoid syndrome, it has a sudden onset and manifests as pink or red discoloration of the skin of the face, neck, and upper trunk. Over time, some patients develop and maintain a persistent cyanotic hue on the face, while during a flush attack, the nose turns purplish-red. The frequency of flushes varies from several times a day to 1–3 or more episodes per hour.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Principles of medical care for patients with Merkel cell carcinoma, small cell lung cancer, and medullary thyroid carcinoma are outlined in the respective clinical guidelines.

Diagnostic criteria:

1. history data;

2. laboratory and instrumental examination data;

3. results of pathological examination of biopsy (surgical) material.

2.1 Complaints and Anamnesis

2.2 Physical Examination

2.3 Laboratory Diagnostics

Comments: PCC should be suspected in the following cases [32]:

• paroxysmal symptoms of PCC/PGL (arterial hypertension (AH), tachycardia, headache, profuse sweating);

• adrenal incidentaloma with native density on CT greater than 10 HU (regardless of the presence of AH);

• PCC/PGL symptoms provoked by medications (dopamine antagonists, opioids, monoamine oxidase inhibitors, serotonin-norepinephrine reuptake inhibitors, corticosteroids, etc.) or increased intra-abdominal pressure (palpation, urination, defecation);

• positive family history of PCC/PGL;

• history of PCC/PGL in the patient;

• presence of any components of hereditary syndromes associated with PCC/PGL.

Comments: the basis of non-invasive laboratory diagnostics for NETs consists of biochemical markers, which are biologically active substances such as hormones, vasoactive peptides, and amines.

Universal markers:

1. serum chromogranin A (CgA) – in all types of NETs (measurement of blood chromogranin A);

2. plasma pancreatic polypeptide (PP) – in pancreatic NETs;

3. serum neuron-specific enolase (NSE) – in lung and thymic NETs (measurement of blood neuron-specific enolase).

4. Serum gastrin (measurement of serum gastrin level) – in well-differentiated gastric NETs.

Specific markers:

1. serum serotonin and 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA) – for the diagnosis of carcinoid syndrome (measurement of serotonin, its precursors and metabolites in blood, and 5-hydroxyindoleacetic acid (5-HIAA) in urine);

2. serum gastrin – for the diagnosis of Zollinger–Ellison syndrome (gastrinoma) (measurement of serum gastrin level);

3. serum insulin, C-peptide, and glucose – for the diagnosis of insulinoma (measurement of plasma insulin level, blood C-peptide level, and blood glucose level); the test is informative only when hypoglycemia is documented (spontaneous or during a 72-hour fasting test);

4. plasma glucagon (with aprotinin) – for the diagnosis of glucagonoma (measurement of blood glucagon level);

5. plasma vasoactive intestinal peptide (VIP) (with aprotinin) – for the diagnosis of VIPoma (Verner–Morrison syndrome);

6. plasma somatostatin (with aprotinin) – for the diagnosis of somatostatinoma (measurement of blood somatostatin level);

7. plasma histamine – for the diagnosis of carcinoid syndrome in lung and gastric NETs (measurement of blood histamine level);

8. serum parathyroid hormone (PTH) – for the diagnosis of hyperparathyroidism in MEN-1 (measurement of blood parathyroid hormone level);

9. plasma adrenocorticotropic hormone (ACTH), urinary free cortisol, and serum cortisol following a 1 mg overnight dexamethasone suppression test at 23:00 – for the diagnosis of ectopic ACTH-producing paraneoplastic syndrome (measurement of blood adrenocorticotropic hormone level, urinary free cortisol level; salivary free cortisol level);

10. serum N-terminal pro-brain natriuretic peptide (pro-BNP) – for detecting carcinoid cardiofibrosis (carcinoid heart disease) (measurement of blood N-terminal pro-brain natriuretic peptide (NT-proBNP) level).

Recommendations on the use of biochemical markers in the comprehensive diagnosis of NETs are presented in Appendix B (Table 15).

In accordance with the guidelines, the diagnosis of a functioning tumor requires mandatory confirmation of hyperfunctional syndrome based on the analysis of a panel of NET biochemical markers. Table 3 summarizes recommendations on the use of biochemical markers considering the present clinical signs, syndromes, and NET type.

Table 3. Biochemical markers in various clinical manifestations of NETs

Comments: Determination of biochemical markers whose basal levels were elevated should be performed every 3 months, as well as in case of worsening specific symptoms, the appearance of new symptoms, or clinical suspicion of disease progression (Fig. 1).

In well-differentiated gastric NETs, the gastrin level is assessed once at the time of diagnosis, off proton pump inhibitors (A02BC proton pump inhibitors) or H2 blockers (A02BA H2-receptor antagonists), to determine the NET type according to the Rindi classification (Type 1, 2, or 3). In Type 1 gastric NETs, the chromogranin A level remains elevated at all stages of treatment due to chronic atrophic gastritis and is not a criterion for NET recurrence [210, 211].

Fig. 1. Biochemical monitoring in patients with NETs (ENETS, 2017)

In some cases, NET markers can be an early sign of recurrence or progression, revealing pathological changes several months before radiological and clinical signs appear.

Detailed recommendations for the serial determination of biochemical markers along with instrumental examination methods for monitoring the tumor process and assessing treatment efficacy are presented in Appendix B (Table 16). In general, follow-up intervals depend on the localization, type, and status of the tumor. Shorter examination intervals are recommended for high tumor grade, large tumor size, advanced disease (liver involvement > 30%, lung and bone metastases), aggressive course with progression within the next few months, severe uncontrolled endocrine symptoms, weight loss, and CgA levels exceeding the upper limit of normal by more than 10 times.

Comments: an NT-proBNP level above the threshold is an indication for an echocardiographic examination.

2.4 Instrumental Diagnostics

The list of examinations is determined by tumor localization. The studies are performed to assess the primary tumor and clarify the extent of the disease. The treatment plan should not be formulated until data on the extent of the tumor process are obtained.

It should be noted that the main feature of NETs is the overexpression of somatostatin receptors on the cell surface, which allows for their visualization using radionuclide diagnostic methods based on receptor-specific radiopharmaceuticals (RPs). Specific and metabolic visualization of these neoplasms is also possible.

• esophagogastroduodenoscopy (*stomach, duodenum);

• colonoscopy (rectum and colon);

• endosonography – for the stomach and duodenum;

• enteroscopy (intestinoscopy);

• video capsule small bowel endoscopy;

• fibrobronchoscopy (bronchoscopy) [42, 54-56, 200].

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

2.4.1 Radionuclide diagnostics of neuroendocrine tumors

Comment: since neuroendocrine tumor cells are characterized by somatostatin receptor overexpression, the use of radiopharmaceuticals (V09IX: Other radiopharmaceuticals for tumor diagnosis based on synthetic somatostatin analogues (H01CB Somatostatin and analogues)) is justified for diagnosing these neoplasms. This helps select the optimal treatment strategy and make decisions regarding the appropriateness of biotherapy with somatostatin analogues (H01CB Somatostatin and analogues) or radionuclide therapy, provided there is a high level of their expression and/or functional activity. [99, 100-101.]

Comment: ¹⁸F-FDG is an agent for non-specific metabolic imaging. ¹⁸F-FDG is ineffective in well-differentiated NETs, but is successfully used for the diagnosis of advanced neuroblastoma, pheochromocytoma, and paraganglioma (especially with SDHB gene mutation), poorly differentiated NET G3, and NEC.

Comment:¹⁸F-L-DOPA is an imaging agent for the dopaminergic system. This radiopharmaceutical (V09IX: Other radiopharmaceuticals for tumor diagnosis) is less effective for diagnosing metastatic paraganglioma with an SDHB mutation.

Comment: these drugs are norepinephrine analogues** and are incorporated into adrenergic tissues and tumors derived from them. Therefore, indications for their use include the diagnosis of neuroblastoma, pheochromocytoma, paraganglioma, bronchial and small bowel carcinoids, MEN syndromes (MEN2A, MEN2) and treatment planning for neuroblastomas, pheochromocytomas, and paragangliomas with [¹²³I]iobenguane [36, 46, 96].

2.5 Other Procedures

Comments: the diagnostic standard is the pathomorphological examination of biopsy (surgical) material, including: analysis of hematoxylin and eosin-stained tumor tissue sections, immunohistochemical methods (IHC analysis of tumor tissue sections stained with specific antibodies), and analysis of cytological material.

Pathomorphological examination using IHC methods.

The morphological diagnosis of NET is established based on a system of histological criteria included in the WHO classification of tumors, taking into account the specific localization of the lesion. Pathomorphological examinations are performed according to standard morphological parameters, such as differentiation, tumor architecture, growth pattern, cellular and nuclear characteristics, presence of vascular and perineural invasion, necrosis, and the degree of mitotic activity of tumor cells, and must include immunohistochemical examination. For surgical specimens, it is mandatory to indicate the size of the primary focus, its extent to adjacent tissues, and the presence of affected lymph nodes.

Diagnostic features of neuroendocrine differentiation in a tumor include an organoid growth pattern, fine granular chromatin ('salt and pepper' pattern), and the expression of several key neuroendocrine markers detected by IHC examination.

Verification of epithelial and neuroendocrine differentiation of the neoplasm is performed by staining tumor sections with antibodies to pancytokeratin AE1/3, cytokeratin 18, cytokeratin 20 (for Merkel cell carcinoma), synaptophysin, and chromogranin A (CgA). If one of the neuroendocrine differentiation markers is absent, antibodies to CD56 are used for additional staining. In complex diagnostic cases when evaluating metastases with an unidentified primary focus, transcription factors of intestinal, pulmonary, and pancreatic differentiation (CDX-2, TTF-1, PDX-1) are used.

According to modern concepts, pheochromocytoma, like any NET, has metastatic potential. Previously existing categories of benign and malignant pheochromocytoma have been revised in favor of risk-stratification approaches (WHO Classification of Tumors, 2017). The malignant potential of pheochromocytoma/paraganglioma must be assessed using currently existing scoring systems (PASS or GAPP) and by performing an IHC examination.

For adrenal tumor(s), with the exception of ordinary clear cell adenomas of the adrenal cortex, an IHC examination is indicated. The purpose of the study is the differential diagnosis of the tissue origin of the tumor and determination of proliferative activity [40].

• It is recommended that all patients undergo determination of proliferative activity using the Ki-67 labeling index via immunohistochemistry to determine the level of proliferative activity of tumor and/or metastatic cells, assess the aggressiveness of the process, and evaluate drug sensitivity [3, 48, 49].

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

Comments: this parameter is important to determine not only in the primary tumor, but also during tumor progression via repeat biopsies.

• For pheochromocytoma and paraganglioma with a Ki-67 index > 10%, it is recommended to have the slides reviewed at a reference center [130].

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

Comments: this parameter is important to determine not only in the primary tumor, but also during tumor progression via repeat liver biopsies.

• All patients with PCC/PGL with suspected MEN syndrome, von Hippel-Lindau syndrome, hereditary paraganglioma syndrome type 4, or other syndromes are recommended to consult a geneticist to discuss genetic testing. [37, 63].

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

Comments: genetic screening may be based on specific phenotypic features of the disease and family history data; however, in their absence, it is preferable to use a comprehensive gene panel (currently sets of 14–18 candidate genes). Patients must be counseled on the purpose and results of genetic testing before and after the procedure, emphasizing the importance of examining all first-degree relatives.

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

Principles of medical care for patients with Merkel cell carcinoma, small cell lung cancer, and medullary thyroid carcinoma are outlined in the respective clinical guidelines.

3.1. Surgical treatment (localized, resectable locally advanced, and resectable metastatic neuroendocrine tumors)

Comments: surgical interventions for NETs are performed in compliance with basic oncological principles (radicality, ablastics, lymphadenectomy).

Types of surgical interventions:

• endoscopic mucosal resection for small polypoid NETs of the stomach, duodenum, colon, and rectum;

• removal of the primary tumor + regional lymphadenectomy (standard procedures);

• combined and complex operations (unclassified) for resectable locally advanced NETs;

Features of surgical treatment for well-differentiated GI NETs of specific localizations [211-215]:

• Gastric NETs type 1-2 – endoscopic mucosal resection for G1-G2 tumors > 10 mm in size, including multiple and recurrent NETs; for tumors > 20 mm, muscularis propria invasion, or lymph node metastases – gastric resection or gastrectomy;

• Gastric NETs type 3 – endoscopic mucosal resection for G1 tumors ≤10 mm in size. Gastric resection or gastrectomy in all other cases: G1 > 10 mm, G2-G3, muscularis propria invasion, lymph node metastases;

• Duodenal NETs – endoscopic mucosal resection for non-functioning G1 NETs ≤10 mm in size. Duodenal resection or pancreatoduodenal resection in all other cases: size > 10 mm, functioning NETs, G2-G3, muscularis propria invasion;

• Non-functioning pancreatic NETs – G1-G2 NETs ≤10 mm in size without main pancreatic duct dilation are subject to active surveillance. For G1 NETs > 10 mm and ≤20 mm without main pancreatic duct dilation, active surveillance or enucleation is possible. For NETs > 20 mm or main pancreatic duct dilation – various surgical options with lymphadenectomy;

• Small bowel NETs G1-G2 – right hemicolectomy (localization within 20 cm of the ileocecal valve) or small bowel resection (localization proximal to 20 cm from the ileocecal valve). Metastatic small bowel NETs G1-2 – removal of the primary tumor (in all patients) and resectable distant metastases;

• Appendiceal NET G1/G2 ≤ 10 mm – appendectomy; for appendiceal NET G1-2 with tumor size >10 mm but ≤20 mm in the presence of additional risk factors (>3 mm mesoappendiceal invasion, R1, lymphovascular invasion) and an expected life expectancy >15 years, as well as for appendiceal NET >20 mm or G3 – right hemicolectomy;

• Colon NET G1 ≤ 10 mm – endoscopic resection. In all other cases – surgical treatment (resection of the corresponding bowel segment or hemicolectomy);

• Rectal NET G1-G3 ≤ 10 mm, rectal NET G1-G2 >10 mm, but ≤ 20 mm – endoscopic mucosal resection or transanal excision. Surgical treatment (resection or extirpation of the rectum) in all other cases: G3 > 10 mm, G1-G2 > 20 mm, invasion into the muscular layer, lymph node metastases, R1 after endoscopic resection or transanal excision;

Features of surgical treatment for well-differentiated metastatic NETs:

• simultaneous or sequential removal of the primary tumor and resectable distant metastases

• removal or destruction of distant metastases; cytoreductive surgery for functioning/hormone-producing tumors;

• for non-functioning NETs, when it is possible to achieve removal of more than 90% of the tumor tissue; for isolated liver involvement by NET metastases – liver resection of various volumes (atypical, segmental, hemihepatectomy, extended hemihepatectomy), including via laparoscopic approach;

• in a limited number of young, fit patients with high-grade well-differentiated NETs with isolated bilobar liver metastases and the impossibility of using other local treatment modalities, liver transplantation may be considered upon decision of a multidisciplinary team (in accordance with the Milan criteria).

3.2. Adjuvant Therapy for NETs

• Routine use of postoperative therapy in G_1–2 NETs is not recommended [53].

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

Comment: administering 4 cycles of adjuvant chemotherapy significantly improves progression-free and overall survival in extrapulmonary NEC.

Comment: administering 4 cycles of adjuvant chemotherapy significantly improves progression-free survival in pancreatic NENs [181]. Most retrospective studies have not demonstrated the efficacy of this approach, which is due to unbalanced group characteristics; therefore, the decision to prescribe adjuvant chemotherapy in this subgroup of patients should be made individually by a multidisciplinary team, with preferred regimens being TemCap, XELOX, or FOLFOX, as they are most effective in metastatic NETs [182].

3.3. Medical therapy for patients with unresectable and metastatic NETs of all sites

3.3.1 Well-differentiated neuroendocrine tumors G₁, G2

Comments: somatostatin analogues (H01CB Somatostatin and analogues) are the generally accepted first-line antiproliferative therapy for NETs based on two phase III placebo-controlled trials, PROMID and CLARINET. These studies were conducted independently and differed in patient characteristics and endpoint definitions. In the PROMID study, among patients with well-differentiated midgut NETs (G1, Ki67<2%), the median PFS with octreotide** was 14.3 months versus 6 months in the placebo group (P=0.000072) [5]. In the CLARINET OLE extended prospective study, the median PFS in patients receiving lanreotide** 120 mg was 38.5 months [95% CI: 30.9-59.4] [6, 105]. The CLARINET study featured a more heterogeneous cohort of patients with GEP-NETs, reflecting real-world clinical practice: by localization (midgut and pancreatic NETs, NETs of unknown primary origin), by grade (G1-70%, G2-30%), with the Ki-67 proliferation index varying up to 10%. For long-acting formulations of somatostatin analogues (H01CB Somatostatin and analogues), treatment is initiated with a short-acting drug. Short-acting octreotide** is administered subcutaneously at a dose of 100 mcg 3 times daily for 2 weeks; then, if tolerability is satisfactory, long-acting formulations can be prescribed – long-acting octreotide** 30 mg i.m. or lanreotide** 120 mg subcutaneously every 28 days

Long-acting octreotide** 30 mg is indicated for the treatment of gastroenteropancreatic neuroendocrine tumors according to the instructions.

In case of progression, higher doses of long-acting octreotide** of 40 mg and above can be used. [115] The 10 mg dose is not used independently and exists solely for dose escalation of the recommended dose. For lanreotide**, the recommended dose is 120 mg subcutaneously every 4 weeks [5–8]; upon progression, the injection interval may be shortened to 3–2 weeks or the dose escalated to 180 mg [31]. In the CLARINET FORTE prospective open-label phase II study, shortening the administration interval of lanreotide** 120 mg to 14 days in patients with progressing NETs achieved a median PFS of 8.3 (5.6; 11.1) months in the midgut NET group and 5.6 (5.5; 8.3) months in the pancreatic NET group, while maintaining treatment safety and patient quality of life [106]. Upon tumor progression, octreotide** can be switched to lanreotide** and vice versa [5–8, 110, 111]. Additionally, in case of intolerance to one of the drugs, the other may be prescribed [31].

• For patients with unresectable well-differentiated GI NETs (G1, G2), pancreatic NETs, or lung/mediastinal carcinoids lacking somatostatin receptors, it is recommended to consider the use of #interferon alfa-2b** at 3-5 million IU 3 times a week subcutaneously, starting dose 3 million IU 3 times a week subcutaneously, with good tolerability and insufficient efficacy, dose escalation to 5 million IU 3 times a week subcutaneously is possible to control symptoms of hormonal hypersecretion [9, 74-75, 115, 116].

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

• For patients with unresectable well-differentiated NETs (G1, G2) or lung/mediastinal carcinoids lacking somatostatin receptors in the 1st line of therapy, it is recommended to prescribe targeted therapy:

#everolimus** at a dose of 10 mg/day (for all localizations) daily continuously for a long time, without interruption.

#sunitinib** 37.5 mg (only for pancreatic NETs or pheochromocytoma/paraganglioma), daily continuously for a long time, without interruption [9, 10, 28, 74, 75].

LoE CLevel of evidence - C (grade of recommendation - 4).

• For patients with unresectable well-differentiated NETs (G1, G2) in the 2nd line after treatment with somatostatin analogues (H01CB Somatostatin and analogues) OR in the 1st line with a high tumor burden, it is recommended to prescribe targeted therapy in combination with somatostatin analogues:

#sunitinib** 37.5 mg only for pancreatic NETs, daily continuously for a long time, without interruption, combined with octreotide** 30 mg intramuscularly or #lanreotide** 120 mg subcutaneously every 4 weeks, or as monotherapy for pheochromocytoma/paraganglioma [10, 28, 29, 117];

#everolimus** at a dose of 10 mg/day daily continuously for a long time for all NET localizations except pheochromocytoma/paraganglioma, combined with #octreotide** 30 mg or lanreotide** 120 mg every 4 weeks (G1, Ki-67 ≤2%) [11–13, 28, 30, 73, 118].

LoE CLevel of evidence - C (grade of recommendation - 4).

Comments: if the 37.5 mg dosage of sunitinib** is unavailable (25 mg and 12.5 mg), a schedule of 50 mg daily for 4 weeks with a 2-week break may be used.

LoE ALevel of evidence - A (grade of recommendation - 5).

• Patients with unresectable well-differentiated (G1, G2) NETs may be recommended #pazopanib** 800 mg orally daily continuously for a long time for G1-G2 NETs of all localizations, and for lung/mediastinal carcinoids it can be used in combination with long-acting somatostatin analogues (H01CB Somatostatin and analogues). [112, 131, 148, 183]

LoE CLevel of evidence - C (grade of recommendation - 4).

Comments: Peptide receptor radionuclide therapy (PRRT) is a form of molecularly targeted radiation therapy that provides selective and systemic delivery of an unsealed source of ionizing radiation to tumor cells aiming for a cytotoxic radiation antitumor effect. The primary radiopharmaceutical (RP) used for PRRT of NETs expressing somatostatin type 2 receptors is ¹⁷⁷Lu-DOTA-TATE, which is a peptide ligand (somatostatin analogue Octreotate) and a therapeutic beta-emitting isotope ¹⁷⁷Lu covalently linked by a chelator (DOTA).

In the large-scale prospective phase III NETTER-1 study, 229 patients with progressive midgut NETs were randomized to treatment with either ¹⁷⁷Lu-DOTA-TATE or high-dose octreotide**. The NETTER-1 results demonstrated that treatment with ¹⁷⁷Lu-DOTA-TATE was associated with a significant improvement in PFS (not reached compared with 8.4 months in the control group, p <0.0001). Objective tumor responses were observed in 18% of patients receiving ¹⁷⁷Lu-DOTA-TATE versus 3% in the control group (p<0.001).

In 2021, final overall survival and long-term safety results from the NETTER-1 trial were published: treatment with ¹⁷⁷Lu-DOTA-TATE did not improve median overall survival (OS) compared with high-dose long-acting octreotide**. Although the primary overall survival endpoint did not reach statistical significance, the 11.7-month difference in median OS with ¹⁷⁷Lu-DOTA-TATE treatment compared with high-dose long-acting octreotide** alone may be considered clinically meaningful.

Another large study investigated the long-term efficacy, survival, and toxicity of ¹⁷⁷Lu-DOTA-TATE in a cohort of 610 Dutch patients with metastatic GEP and bronchial NETs. PFS and OS for all patients were 29 months [95% CI, 26-33 months] and 63 months (95% CI, 55-72 months), respectively. Other smaller studies also demonstrated an improvement in OS (58.8 months, n=114) and median PFS (20.1 months for typical disease and 15.7 months for atypical; n=34) with PRRT in patients with advanced bronchopulmonary NETs.

A meta-analysis of 18 studies involving 1,920 patients with unresectable metastatic NETs treated with ¹⁷⁷Lu-DOTA-TATE PRRT showed that the overall response rate was 29-31%, and the overall disease control rate was 74-81%. Recommended ¹⁷⁷Lu-DOTA-TATE PRRT regimen: administered activity 5.55-7.4 GBq (150-200 mCi), number of cycles 3-5, interval between cycles 6-12 weeks.

Patients with hormone-secreting tumors should continue using octreotide** or lanreotide** along with ¹⁷⁷Lu-DOTA-TATE. The use of long-acting somatostatin analogues such as lanreotide** and octreotide** is not recommended for 4–6 weeks prior to each administration of ¹⁷⁷Lu-DOTA-TATE. Short-acting somatostatin analogues (somatostatin and its analogues) should be discontinued 24 hours prior to initiating treatment with ¹⁷⁷Lu-DOTA-TATE. Somatostatin analogues (both short- and long-acting) can be resumed 4–24 hours after each administration of ¹⁷⁷Lu-DOTA-TATE.

In January 2024, final results of the phase III NETTER-2 study were presented. The study enrolled 226 patients with metastatic well-differentiated GEP-NETs grade 2 or 3 and a Ki-67 index of ≥10% and ≤55%. Pancreatic tumors accounted for 55%, and small intestinal tumors for 29%. Patients in the experimental arm (n=151) received ¹⁷⁷Lu-DOTA-TATE with standard-dose octreotide** (30 mg) every 8 weeks. Patients in the control arm (n=75) received high-dose octreotide** monotherapy (60 mg) every 4 weeks. The NETTER-2 trial demonstrated the following results: the use of ¹⁷⁷Lu-DOTA-TATE reduced the risk of disease progression or death by 72% (p<0.0001), with the benefit being independent of age, sex, race, tumor grade, and primary localization; the ORR was 43% in the ¹⁷⁷Lu-DOTA-TATE group and 9.3% in the control group, with complete responses achieved in 5.3% and 0%, respectively; patients receiving PRRT had an almost eightfold higher likelihood of response (OR=7.81) compared to those receiving high-dose octreotide**; median PFS increased from 8.5 months to 22.8 months with the combination of ¹⁷⁷Lu-DOTA-TATE and long-acting octreotide** formulations.

Table 6. Chemotherapy regimens

*Indicated for neuroendocrine tumors of any localization.

¹No more than 3000 mg per course.

Comments: the multicenter, randomized, double-blind, placebo-controlled phase III TELESTAR trial included 135 patients with metastatic neuroendocrine tumors and a documented history of carcinoid syndrome not controlled by high doses of somatostatin analogues (H01CB Somatostatin and analogues), manifested by 4 or more bowel movements per day despite stable doses of somatostatin analogues for at least 3 months prior to enrollment [113, 114, 119–120].

Patients were randomized in a 1:1:1 ratio into 3 groups receiving placebo (3 times daily) + somatostatin analogues (H01CB Somatostatin and analogues), telotristat (250 mg 3 times daily) + somatostatin analogues (H01CB Somatostatin and analogues), or telotristat (500 mg 3 times daily) + somatostatin analogues (H01CB Somatostatin and analogues) for 12 weeks. From baseline to week 12, the mean reduction in daily bowel movement frequency for placebo, telotristat (250 mg), and #telotristat (500 mg) was -0.9, -1.7, and -2.1, respectively. In addition, both telotristat doses significantly reduced mean urinary 5-HIAA excretion compared to placebo at week 12 (P < 0.001).

In the TELEPRO real-world clinical practice study, patients treated with telotristat experienced a reduction in diarrhea episodes and other symptoms of carcinoid syndrome [114].

3.3.2 Well-differentiated neuroendocrine tumors G₃

Table 7. Chemotherapy regimens [14, 15, 18–20]

*Indicated for neuroendocrine tumors of any localization.

¹Maximum 3000 mg per course.

Comments: The multicenter, randomized, double-blind, placebo-controlled phase III trial TELESTAR enrolled 135 patients with metastatic neuroendocrine tumors and a documented history of carcinoid syndrome refractory to high doses of somatostatin analogs, manifested by 4 or more bowel movements per day despite stable doses of somatostatin and its analogs for at least 3 months prior to study enrollment. [113, 114, 119-120]. Patients were randomized in a 1:1:1 ratio into 3 groups receiving placebo (t.i.d.) + somatostatin analogs (H01CB Somatostatin and analogs), telotristat (250 mg t.i.d.) + somatostatin analogs, or #telotristat (500 mg t.i.d.) + somatostatin analogs for 12 weeks. From baseline to week 12, the mean reduction in daily stool frequency for placebo, telotristat (250 mg), and #telotristat (500 mg) was -0.9, -1.7, and -2.1, respectively. In addition, both doses of telotristat significantly reduced mean urinary 5-HIAA excretion compared with placebo at week 12 (P < 0.001). In the TELEPRO real-world study, patients receiving telotristat experienced a reduction in diarrhea episodes and other symptoms of carcinoid syndrome. [114].

Comments: In January 2024, final results of the phase III NETTER-2 study were presented. The study included 226 patients with metastatic well-differentiated GEP-NET grade 2 or 3 and with a Ki67 index ≥10% and ≤55%. Pancreatic tumors accounted for 55%, small intestinal tumors for 29%. Patients in the experimental group (n=151) received ¹⁷⁷Lu-DOTA-TATE with standard-dose #octreotide** (30 mg) every 8 weeks. Patients in the control group (n=75) received only high-dose octreotide** therapy (60 mg) every 4 weeks. Administration of ¹⁷⁷Lu-DOTA-TATE resulted in a 72% reduction in the risk of disease progression or death (p < 0.0001), with the benefit independent of tumor grade and localization; the ORR was 43% in the ¹⁷⁷Lu-DOTA-TATE group and 9.3% in the control group, with complete responses achieved in 5.3% and 0%, respectively; patients receiving PRRT had an almost eightfold higher probability of response (OR = 7.81) compared to patients receiving high-dose octreotide**; median PFS increased from 8.5 months to 22.8 months with the combination of ¹⁷⁷Lu-DOTA-TATE and prolonged-release formulations of #octreotide**. Given that high doses of octreotide** are not the first-line standard of care for these patients, the control group was chosen inadequately. Therefore, the optimal first-line treatment strategy for these patients—PRRT + somatostatin analogs (H01CB Somatostatin and analogues) or chemotherapy +/- somatostatin analogs (H01CB Somatostatin and analogues)—remains uncertain.

3.3.3 Poorly differentiated neuroendocrine carcinoma (NEC, NEC)

Table 8. Chemotherapy regimens [85-86]

• In case of progression ≥ 4 months after completion of 1st-line chemotherapy, it is recommended to re-induce with platinum-based chemotherapy (L01XA) [206-207].

Leveled recommendation CEvidence level 5Level of recommendation validity – C (evidence level – 5).

• Combinations listed in Table 8 can be recommended as 2nd and subsequent lines. Preferred treatment regimens for GI and pancreatic NEC are FOLFIRI, TemCap [145].

Leveled recommendation CEvidence level 5Level of recommendation validity – C (evidence level – 5).

Comment: The phase II SENECA trial compared the efficacy of CAPTEM and FOLFIRI regimens in the second and subsequent lines of therapy for GI NEC after progression on platinum-based chemotherapy. The study included 53 of 112 planned patients. Disease control ≥ 12 weeks was achieved in 28% and 32% of patients, and 1-year OS was 32% and 28% in the CAPTEM and FOLFIRI groups, respectively. Thus, equivalence of these treatment regimens was demonstrated.

Comment: A small phase II study investigated the efficacy of combination immunotherapy—nivolumab** + ipilimumab**—as second- and later-line therapy for extra-pancreatic NETs and NECs. The study enrolled 32 patients, with a median ki67 of 80%. The objective response rate was 26%. Disease control ≥ 6 months was achieved in 32% of patients [147].

Comments: biotherapy is not used alone as 1st-line therapy, but exists only as an adjunct for symptom control. Long-acting somatostatin analogs (H01CB Somatostatin and analogues) and interferon alfa-2b** (see regimens) have limited value in poorly differentiated neuroendocrine carcinoma and are used for symptom control in addition to chemotherapy in the presence of carcinoid syndrome or when tumor somatostatin receptor status type 2A or 5 is positive.

3.3 Treatment of pheochromocytoma/paraganglioma

Comments: preoperative preparation with alpha-adrenergic blockers and, as indicated, beta-adrenergic blockers is carried out until efficacy criteria are achieved: normalization of blood pressure, achievement of the target heart rate, and elimination of catecholamine excess-induced hypovolemic syndrome.

• Endoscopic adrenalectomy is recommended for patients with PHEO. For large (>6 cm) and invasive tumors, an open approach is preferred to perform adequate exploration and avoid damage to the tumor capsule. The decision on endoscopic intervention in the presence of a large tumor is based on the relevant experience of the surgical team and the feasibility of maintaining the principles ofablastic surgery [35, 92].

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

Comment: for other hereditary syndromes associated with a higher or uncertain malignant potential, organ-sparing surgeries require further study of long-term outcomes [35, 37, 39, 90].

Comments: if the postoperative metanephrine level is positive, perform instrumental diagnostic studies (Section 2.4). For PHEO/PGL with catecholamine hypersecretion, it is recommended to relieve the symptoms of hormonal hyperproduction with alpha-adrenergic blockers and beta-adrenergic blockers [95].

• Due to the high frequency of an indolent course of metastatic PHEO, it is recommended to consider active surveillance in asymptomatic patients with a low tumor burden [90].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

Comments: a wait-and-see approach includes patient evaluation every 3-6 months during the first year, and then once a year in the absence of progression.

• In an indolent, asymptomatic course of metastatic PHEO/PGL with positive somatostatin receptor expression according to immunohistochemistry (IHC) or radionuclide diagnostics and disease progression during active surveillance, it is recommended to consider therapy with somatostatin analogs – prolonged-release octreotide** or lanreotide** (H01CB Somatostatin and analogs) [124].

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

• In metastatic/unresectable PHEO/PGL with a high tumor burden and/or disease progression during active surveillance and/or therapy with somatostatin analogs (H01CB Somatostatin and analogs), it is recommended to consider prescribing the following treatment regimens (Table 9) [89, 117, 123, 124, 133, 209].

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

• In metastatic PHEO/PGL with positive somatostatin receptor expression, as second- and subsequent-line medical therapy, it is recommended to consider PRRT with #177Lu-DOTATATE 5.5-7.4 GBq + prolonged-release octreotide** 30 mg IM (H01CB Somatostatin and analogs) 4–24 hours after each administration (PRRT) for 4 cycles, followed by maintenance therapy with prolonged-release octreotide** 30 mg IM every 28 days until disease progression [124-125], or #Iobenguane [131I] at a single activity of 3.7–11.2 GBq [126].

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

3.5 Other treatment

3.5.1. Optimal symptomatic therapy and supportive care.

• When administering cytotoxic chemotherapy to patients (with neuroendocrine neoplasms), it is recommended to prevent nausea and vomiting using: A04A antiemetics (5-HT3 receptor antagonists (A04AA), neurokinin-1 (NK-1) receptor antagonists, dexamethasone**, gastrointestinal motility stimulants (metoclopramide**), anxiolytics, antipsychotics, proton pump inhibitors, H2-histamine receptor blockers) [149].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: the choice of nausea and vomiting prevention method is determined by the emetogenic potential of the treatment regimen, individual nausea and vomiting threshold, and comorbidities. A detailed algorithm for the prevention and treatment of nausea and vomiting during antineoplastic therapy is presented in the guidelines "Practical guidelines for the prevention and treatment of nausea and vomiting in cancer patients" [184].

• In patients with neuroendocrine neoplasms, the diagnosis of osteoporosis is carried out by X-ray densitometry of the lumbar spine and femur; for the prevention and treatment of osteoporosis, it is recommended to use agents affecting bone structure and mineralization, bone resorption inhibitors (M05B: Drugs affecting bone structure and mineralization) [150].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: A detailed algorithm for the prevention and treatment of bone complications in patients (indicate nosology) is presented in the methodological guidelines "Use of bone-modifying agents for the prevention and treatment of bone pathology in malignant neoplasms" [185].

• In patients with neuroendocrine neoplasms and bone metastases, it is recommended to use agents affecting bone structure and mineralization, bone resorption inhibitors (M05B: Drugs affecting bone structure and mineralization), palliative radiation therapy, and vertebroplasty [150].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: A detailed algorithm for the prevention and treatment of bone complications in patients (indicate nosology) is presented in the methodological guidelines "Use of bone-modifying agents for the prevention and treatment of bone pathology in malignant neoplasms" [185].

• In patients with neuroendocrine neoplasms, for the diagnosis of venous thromboembolic complications, it is recommended to use duplex scanning of the lower extremity veins, angiography, chest computed tomography with intravenous bolus contrast enhancement, and coagulogram [151, 152].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

• In patients with neuroendocrine neoplasms, for the prevention and treatment of venous thromboembolic complications, it is recommended to use medicinal products (anticoagulants (B01A Antithrombotic agents)), physical methods (compression stockings, pneumatic limb compression), and placement of inferior vena cava filters [153].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: a detailed algorithm for the prevention and treatment of venous thromboembolic complications in patients (indicate nosology) corresponds to the principles outlined in the methodological guidelines "Practical guidelines for the prevention and treatment of thromboembolic complications in cancer patients" [186].

• In patients with neuroendocrine neoplasms, when infectious complications are suspected, for pathogen diagnosis and monitoring of treatment efficacy, it is recommended to use bacteriological tests, determination of procalcitonin, presepsin, C-reactive protein, galactomannan levels, acid-base balance and blood gas analysis, chest X-ray, chest computed tomography, and contrast-enhanced computed tomography and magnetic resonance imaging of the abdominal cavity [154].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

• In patients with neuroendocrine neoplasms, for the prevention and treatment of infectious complications and febrile neutropenia, the use of medications is recommended: systemic antibacterial agents (J01CR penicillin combinations, including beta-lactamase inhibitor combinations; J01C beta-lactam antibacterial agents: penicillins; carbapenems; J01XX other antibacterial agents (oxazolidinones, aminoglycosides); P01 antiprotozoal agents; fluoroquinolones; lincosamides and L03AA colony-stimulating factors (standard and pegylated/extended-release forms) [154-156].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: the detailed algorithm for the diagnosis, prevention, and treatment of infectious complications and febrile neutropenia in patients with neuroendocrine neoplasms complies with the principles set forth in the guidelines «Practical Guidelines for the Diagnosis and Treatment of Febrile Neutropenia» [187].

• During antitumor therapy in patients with neuroendocrine neoplasms, correction of hepatotoxicity is recommended: A16AA amino acids and their derivatives: A05 drugs for liver and bile duct diseases, A16AX other drugs for gastrointestinal tract diseases and metabolic disorders [157-158].

Level of Recommendations CLevel of Evidence 3Level of Recommendation C (Level of Evidence – 3)

Comments: the detailed algorithm for correcting hepatotoxicity complies with the principles set forth in the guidelines «Clinical Guidelines for the Correction of Antitumor Therapy-Induced Hepatotoxicity» [188].

• During antineoplastic therapy in patients with neuroendocrine neoplasms, for the diagnosis of cardiovascular complications and monitoring the efficacy of their treatment, it is recommended to determine cardiac biomarkers (assay of blood troponins I, T, blood N-terminal pro-B-type natriuretic peptide (NT-proBNP)), perform an ECG, echocardiography, and Holter cardiac rhythm monitoring [159, 160].

Level of Recommendations CLevel of Evidence 3Level of Recommendation C (Level of Evidence – 3)

• For the prevention and treatment of cardiovascular complications, the use of the following drugs is recommended: C09CA angiotensin II receptor antagonists, C01D vasodilators for heart diseases (C01DA: organic nitrates, magnesium preparations), C08CA: dihydropyridine derivatives, beta-blockers [161, 162].

GGR BLEL 2 Grade of Recommendation B (Level of Evidence – 2)

Comments: the choice of the method for preventing cardiovascular complications is determined by cardiovascular risk factors. A detailed algorithm for the prevention and treatment of cardiovascular complications during antitumor therapy is presented in the guidelines «Practical Guidelines for the Correction of Cardiovascular Toxicity of Antineoplastic Drug Therapy» [189].

• During cytotoxic chemotherapy in patients with neuroendocrine neoplasms, for the prevention and treatment of skin complications, the following are recommended: D11AX other dermatological drugs - moisturizing creams, keratolytic creams, sunscreens, D07: Corticosteroids, dermatological preparations (combined topical corticosteroids), D07C: Corticosteroids, combinations with antibiotics, J01A: tetracyclines, D06: Antibiotics and chemotherapeutics for dermatological use, D07C Corticosteroids combined with antibiotics (topical corticosteroid + antibacterial agent) dermatotropic agents, L04AD: calcineurin inhibitors, antiseptics, D06B antibiotics and chemotherapeutics for topical use in dermatology [163].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: the choice of skin complication prevention method is determined by the various types of dermatological reactions. A detailed algorithm for the prevention and treatment of skin complications is presented in the guidelines «Practical Guidelines for the Medicinal Treatment of Dermatological Reactions in Patients Receiving Antineoplastic Drug Therapy» [190].

• During cytotoxic chemotherapy in patients with neuroendocrine neoplasms, nutritional support is recommended in accordance with the clinical guidelines for nutritional support [164, 165].

GGR BLEL 2 Grade of Recommendation B (Level of Evidence – 2)

Comments: the choice of nutritional support method is determined by the patient's various types of nutritional disorders. A detailed algorithm for the prevention and treatment of skin complications is presented in the guidelines «Practical Guidelines for Nutritional Support in Cancer Patients» [191].

• During cytotoxic chemotherapy in patients with neuroendocrine neoplasms, for the prevention and treatment of nephrotoxicity, the prescription of M04A: anti-gout preparations, including hemodialysis in accordance with the guidelines for the prevention and treatment of nephrotoxicity is recommended [166].

GGR ALEL 1 Grade of Recommendation A (Level of Evidence – 1)

Comments: the choice of method for the prevention and treatment of nephrotoxicity is determined by the various variants of nephropathies and chemotherapy regimens in the patient. A detailed algorithm for the prevention and treatment of nephrotoxicity is presented in the guidelines «Practical Guidelines for

• In the event of immune-mediated adverse events during therapy, treatment of immune-mediated adverse events with the following drugs is recommended: H02AB: glucocorticoids, immunosuppressants, A07: antidiarrheal, intestinal anti-inflammatory and anti-infective agents, J01E: Sulfonamides and trimethoprim [167, 168].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: the choice of the method for preventing and treating immune-mediated adverse events is determined by the severity of the reaction and the localization of the lesion in the patient. A detailed algorithm for the prevention and treatment of immune-mediated adverse events is presented in the guidelines «Practical Guidelines for the Management of Immune-Mediated Adverse Events» [193].

• For the diagnosis of mucositis in patients with neuroendocrine neoplasms, computed tomography of the chest organs, contrast-enhanced computed tomography of the abdominal organs, esophagogastroduodenoscopy, colonoscopy, and microbiological (culture) stool examination for aerobic and facultatively anaerobic microorganisms and for the causative agent of Clostridioides difficile infection are recommended [169].

Level of Recommendations CLevel of Evidence 3Level of Recommendation C (Level of Evidence – 3)

• During cytotoxic chemotherapy in patients with neuroendocrine neoplasms, for the prevention and treatment of mucositis, the use of the following drugs is recommended: D07A glucocorticoids, somatostatin analogues (H01CB Somatostatin and analogues), antidiarrheal agents (A07X: Other antidiarrheal drugs), antiprotozoal drugs, J01XA: Glycopeptide antibacterial drugs, local anesthetics, antidepressants, nasogastric tube placement [170].

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

Comments: the choice of the method for preventing and treating mucositis is determined by the severity of the reaction and the localization of the lesion in the patient. A detailed algorithm for the prevention and treatment of mucositis is presented in the guidelines «Practical Guidelines for the Treatment and Prevention of Mucositis» [194].

• During cytotoxic chemotherapy in patients (with neuroendocrine neoplasms), the treatment of anemia with blood transfusions, parenteral and oral iron preparations, hematopoiesis stimulants (B: Blood and blood-forming organs), and vitamins is recommended [171, 172].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: the choice of anemia treatment method is determined by the severity of vitamin and iron deficiencies in the patient. A detailed algorithm for the prevention and treatment of anemia is presented in the guidelines «Practical Guidelines for the Treatment of Anemia in Malignant Neoplasms» [195].

• During cytotoxic chemotherapy in patients with neuroendocrine neoplasms, the treatment of anorexia-cachexia syndrome with the following drugs is recommended: progestogens, H02AB glucocorticoids, antiemetics, R06A systemic antihistamines, N02CC Selective serotonin 5-HT1 receptor agonists [173].

Level of Recommendations CLevel of Evidence 3Level of Recommendation C (Level of Evidence – 3)

Comments: the choice of treatment method for anorexia-cachexia syndrome is determined by the severity of vitamin and iron deficiencies in the patient. A detailed algorithm for the prevention and treatment of anorexia-cachexia syndrome is presented in the guidelines «Practical Guidelines for the Treatment of Anemia in Malignant Neoplasms» [196].

• For prolonged (over 6 hours) infusions of L01 antineoplastic drugs or in case of poor peripheral vein condition in patients with neuroendocrine neoplasms during cycle treatment, the use of central venous access and infusion pumps is recommended [174].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: the choice of central access option is determined by the planned duration of the entire course of treatment, patient preferences, and anatomical features. For prolonged (over 3 months) courses of therapy, implantation of a subcutaneous venous port system is most convenient. For shorter periods, a peripherally inserted central catheter can serve as an alternative.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

• in the 1st and 2nd years – 1 time in 3 months;

• in the 3rd to 5th years – 1 time in 6 months;

• after 5 years – 1 time per year [54-57].

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

Comments: The objective of monitoring is the early detection of disease progression for the purpose of early initiation of drug therapy or surgical treatment in surgically resectable clinical situations. The scope of examination is determined taking into account the location, type, and status of the tumor – see Table 16 in Appendix B.

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 dated November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Protecting the Health of Citizens 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, which is approved by the authorized federal executive body;

2. in accordance with the procedure for rendering care in the profile "oncology", mandatory for implementation throughout the Russian Federation by all medical organizations; on the basis of these clinical guidelines;

3. 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.

In case of suspicion or detection of an oncological disease in a patient, general practitioners, district general practitioners, general family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the established manner for a consultation to an outpatient oncological care center or to a primary oncological office or primary oncological department of a medical organization to receive primary specialized medical 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.

If it is impossible to collect biopsy (surgical) material or perform other diagnostic tests at 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 in the pathoanatomical bureau (department).

If an oncological disease is suspected and/or detected 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 oncological diseases to determine management tactics and the need for additional other methods of specialized antitumor treatment.

The oncologist of the outpatient oncological care center (primary oncological office, primary oncological department) shall refer the patient to an oncological dispensary or medical organizations providing medical care to patients with oncological diseases to clarify the diagnosis (if the oncologist of the outpatient oncological care center, primary oncological office, or primary oncological department is unable to establish the diagnosis, including the extent of the oncological process and the stage of the disease) and to receive specialized, including high-tech, medical care.

The timeframe for initiating specialized, except for high-tech, medical care for 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 NET or 14 calendar days from the date of establishing a preliminary diagnosis of the NET (in the absence of medical indications for performing pathomorphological examinations in outpatient settings).

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 hold a license, have the necessary material and technical base and certified specialists, in inpatient and day-hospital 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 established by a concilium of oncologists and radiation therapists, involving other medical specialists if necessary. The decision of the medical concilium is formalized in a protocol, signed by the participants of the medical concilium, 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 "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. presence of indications for specialized antineoplastic treatment (surgical intervention, radiation therapy, including contact therapy, teletherapy, and other types of radiation therapy, 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 providing specialized, including high-tech, medical care in a 24-hour or day hospital setting, provided there are no treatment complications requiring drug correction and/or inpatient medical interventions;

2. refusal by the patient or their legal representative of specialized (including high-tech) medical care in an inpatient or day-inpatient setting prescribed by the concilium of the cancer-care medical organization, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or inpatient medical interventions;

3. the need to transfer the patient to another medical organization of the appropriate profile for medical care. 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 planned receiving medical organization.

7. Additional Information

7.1 Main requirements for collecting biological material and investigating markers of neuroendocrine tumors

1. Blood collection for biochemical markers is carried out in the morning hours before any diagnostic and therapeutic procedures (including biotherapy), strictly observing the necessary preanalytical factors, including a 12-hour fast.

2. Blood collection to determine the level of metanephrines in the blood is recommended to be performed in a recumbent position after a 30-minute horizontal rest.

3. Determination of chromogranin A in the blood and investigation of serum gastrin levels must be performed after proton pump inhibitors (A02BC) for 1–2 weeks, H2-histamine receptor blockers (A02BC) for 1–2 days, prior to the administration of somatostatin and analogues (H01CB).

4. Investigation of the level of serotonin, its precursors and metabolites in the blood, and investigation of the level of 5-hydroxyindoleacetic acid (5-HIAA) in the urine must be carried out after excluding a number of food products (bananas, avocados, plums, pineapples, eggplants, tomatoes, walnuts, chocolate, coffee) and medicines affecting the levels of the studied parameters for 2–3 days.

5. To determine specific peptides (somatostatin, PP, VIP, glucagon), it is necessary to collect blood into special vacuum test tubes for venous blood collection with K2EDTA, aprotinin / with K3EDTA and aprotinin.

6. Collection of 24-hour urine for the investigation of the level of 5-hydroxyindoleacetic acid (5-HIAA) in the urine is carried out using a preservative (citric acid).

7. Serial marker assays must be performed using identical test systems at the base of a single specialized laboratory. When switching to a different test system, patients must be established with new baseline levels. Results and reference ranges obtained using test systems from different manufacturers must not be compared.

8. Instructions for patient preparation for biochemical marker testing are issued at the laboratory.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Artamonova E.V., MD, Professor, Head of the Department of Antitumor Drug Therapy No. 1 at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

2. Beltsevich D.G., MD, Professor, Chief Researcher at the Endocrinology Research Center of the Russian Ministry of Health.

3. Bokhyan V.Yu., MD, Head of Surgical Department No. 2 (Tumor Diagnostics) at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

4. Geliashvili T.M., PhD, Head of the Radionuclide Therapy Department within the Radionuclide Diagnostics and Therapy Division at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

5. Gorbunova V.A., MD, Professor, Leading Researcher at the Chemotherapy Department at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

6. Delektorskaya V.V., MD, Professor, Leading Researcher, Pathologist at the Pathoanatomical Department at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

7. Dolgushin M.B., MD, Professor of RAS and RMAPO, Head of the PET Department at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

8. Egorov A.V., MD, Professor, Head of the Department of Oncological Surgery, University Hospital No. 1, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health.

9. Emelyanova G.S., PhD, Assistant at the Department of Oncology, Faculty of Additional Professional Education, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health.

10. Zhukova L.G., MD, Deputy Director of the A.S. Loginov Moscow Clinical Scientific Center of the Moscow Healthcare Department

11. Zhulikov Ya.A., Oncologist at the Department of Antitumor Drug Therapy No. 1, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

12. Kaspshik S.M., Physician at the PET Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

13. Krylov A.S., PhD, Associate Professor, Head of Radionuclide Diagnostics Department No. 1, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health;

14. Kuzminov A.E., PhD, Researcher at Biotechnology Department No. 1, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

15. Lyubimova N.V., ScD, Leading Researcher at the Laboratory of Clinical Biochemistry, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Professor at the Department of Biochemistry and Laboratory Diagnostics, Faculty of Additional Professional Education, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health.

16. Markovich A.A., PhD, Senior Researcher at the Outpatient Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

17. Melnichenko G.A., MD, Professor, Academician of the RAS, Deputy Director for Research, Endocrinology Research Center of the Ministry of Health of the Russian Federation.

18. Orel N.F., MD, Professor at the Department of Oncology and Palliative Medicine, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

19. Orlov S.V., Corresponding Member of the RAS, MD, Professor, Leading Researcher at the Oncology Department, Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health.

20. Orlova K.V., PhD, Senior Researcher at the Biotherapy Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

21. Orlova R.V., MD, Professor, Head of the Department of Oncology, Faculty of Medicine, Saint Petersburg State University, Chief Clinical Oncology Specialist at St. Petersburg City Clinical Oncology Dispensary.

22. Pronin A.I., PhD, Head of the Radionuclide Diagnostics and Therapy Division, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

23. Romanov I.S., PhD, Senior Researcher at the Head and Neck Tumors Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

24. Trifanov V.S., PhD, Senior Researcher, Rostov Research Institute of Oncology of the Russian Ministry of Health.

25. Khomyakov V.M., Head of the Thoracoabdominal Surgery Department, Thoracoabdominal Oncosurgery Division, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

26. Petrov L.O., Head of the Department of Radiation and Surgical Treatment of Abdominal Diseases, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

27. Pirogov S.S., Head of the Endoscopy Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

28. Fedenko A.A., Head of the Tumor Drug Treatment Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

29. Bolotina L.V., Head of the Chemotherapy Department, Tumor Drug Treatment Division, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

30. Falaleeva N.A., Head of the Malignant Tumor Drug Treatment Division, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

31. Filonenko E.V., Head of the Center for Laser and Photodynamic Tumor Diagnostics and Therapy, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

Healthcare Organization Section:

1. Nevolskikh A.A., MD, Deputy Director for Medical Work, A.F. Tsyb Medical Radiological Research Center — branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

2. Khailova Zh.V., 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.

3. Ivanov S.A., MD, Professor, Corresponding Member of the RAS, Honored Doctor of the RF, Director of the A.F. Tsyb Medical Radiological Research Center — branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Chief freelance Oncologist of the Central Federal District of the Russian Ministry of Health.

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

No conflicts of interest.

All working group members have confirmed the absence of conflicts of interest/financial support that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• oncologists;

• surgeons;

• radiologists;

• endocrinologists;

• pathologists;

• medical students, residents, and graduate students.

Methods used for evidence collection/selection: electronic database searches; analysis of current domestic and international scientific developments on the issue; synthesis of practical experience from Russian and foreign specialists.

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

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

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

Procedure for updating clinical guidelines.

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

Methods used to formulate 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 has been reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations is accessible and understandable.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and the resulting changes made to the recommendations were logged. If no changes were made, the reasons for refusing to make changes were logged.

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

Clinical guideline updates: updates are performed at least once every 3 years, taking into account new information on the diagnosis and management of patients with NET. The decision to update is made by the Russian Ministry of Health based on proposals submitted by medical professional non-profit organizations. The submitted proposals must take into account the results of comprehensive assessments of drugs and medical devices, as well as the results of clinical approbation.

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

The result of this evaluation affects the level of evidence assigned to the publication, which in turn affects the strength of the resulting recommendations.

Appendix A3. Reference Materials

Current instructions for medical product use are available on the official website of the Russian Ministry of Health http://grls.rosminzdrav.ru/Default.aspx

Appendix B. Physician Action Algorithms

Block 1. Primary treatment of resectable GASTROINTESTINAL NETs.

Block 3. Treatment selection algorithm for recurrent and metastatic NETs

Table 15. Recommendations on the use of NET markers (ENETS Consensus Guidelines, 2017)

Table 16. Recommendations for lifelong follow-up of patients with NENs depending on tumor localization, type, and status

Appendix C. Patient Information

1. If body temperature rises to 38 °C or higher:

• contact an oncologist (chemotherapist).

2. In case of stomatitis:

• diet with mechanical and thermal sparing of the mucosa;

• frequent mouth rinsing (every hour) with chamomile, oak bark, or sage decoctions, lubricate the oral cavity with sea buckthorn (peach) oil;

• perform oral cavity care as prescribed by the oncologist

3. In case of diarrhea:

• diet – exclude fatty, spicy, smoked, sweet, dairy, and high-fiber foods. Lean meats, flour products, fermented dairy products, and rice water are permitted. Drink plenty of fluids.

• take medications as prescribed by the oncologist

4. In case of nausea:

• take medications as prescribed by the oncologist

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

Appendix G1. WHO Performance Status Scale/ECOG

Russian title: WHO/ECOG Performance Status Scale

Original title: The ECOG Scale of Performance Status

Source: Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group // Am. J. Clin. Oncol. 1982. Vol. 5, № 6. P. 649–65

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Content and interpretation: