List of Abbreviations
MTC – medullary thyroid carcinoma
MEN – multiple endocrine neoplasia
EBRT – external beam radiotherapy
CT – computed tomography
CEA – carcinoembryonic antigen
MRI – magnetic resonance imaging
PET – positron emission tomography
FNA – fine-needle aspiration biopsy
US – ultrasound examination
TG – thyroid gland
RET – rearranged during transfection
GI – gastrointestinal tract
EBRT – external beam radiotherapy
Terms and Definitions
Central lymphadenectomy – surgical removal of regional lymph nodes and surrounding adipose tissue of level VI of the neck, including prelaryngeal (Delphian), pretracheal, and paratracheal lymph nodes on both sides.
TIRADS (Thyroid Imaging Reporting and Data System) – a standardized system for describing thyroid ultrasound protocols.
Bethesda Thyroid Classification, 2009, 2017, 2023 – a standardized system for describing thyroid fine-needle aspiration cytology protocols.
RECIST 1.1 – Response Evaluation Criteria in Solid Tumors, version 1.1.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Medullary thyroid carcinoma (MTC) is a tumor arising from calcitonin-secreting parafollicular C cells of the thyroid gland, which originate from the neuroectoderm, i.e., an embryonic layer distinct from the mesodermal origin of thyroid A and B cells [1].
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
The etiology of MTC as part of multiple endocrine neoplasia type 2 (MEN2) syndrome is associated with a mutation (pathogenic variant) in the RET gene, which encodes a transmembrane tyrosine kinase receptor. Activation of this receptor leads to uncontrolled C-cell proliferation.
The RET gene consists of 20 exons. Hereditary MTC is associated with pathogenic variants in exons 5, 7–11, 13–16, most commonly in exons 10, 11, 13–16, which are represented by missense mutations (single nucleotide substitutions), and less commonly by deletions or insertions. The disease is inherited in an autosomal dominant manner. Clinical manifestations of MEN2 syndrome depend on the localization of the mutation in the RET gene. These include Sipple syndrome (MEN2A) and Gorlin syndrome (MEN2B).
The most common hereditary variant is MEN2A syndrome. MTC as the primary manifestation of this syndrome develops between the ages of 5 and 25 years, and the phenotypic penetrance of MTC in MEN2A is 100%. Unilateral or bilateral pheochromocytoma and primary hyperparathyroidism develop in 55–75% and 15–30% of cases, respectively. The rarest manifestations are Hirschsprung's disease (colonic aganglionosis) and cutaneous lichenoid amyloidosis.
Previously, isolated familial MTC was distinguished (now considered a variant of MEN2A), which is characterized by isolated thyroid involvement (typically across multiple generations without other manifestations of classical MEN2A syndrome). However, cases of late-onset pheochromocytoma have been described in probands from families with familial isolated MTC. Therefore, most researchers suggest considering familial MTC a variant of MEN2A syndrome with low pheochromocytoma penetrance. MTC in this form typically develops later, has a less aggressive course, and its phenotypic penetrance may not be absolute (some patients with the mutation do not develop MTC).
The most aggressive course of MTC is observed in MEN2B syndrome. Other manifestations of MEN2B include early-onset pheochromocytoma (starting from 12 years of age) and striking physical phenotypic features, including a marfanoid habitus, joint hypermobility, multiple ganglioneuromas of the conjunctiva, mucous membrane of the tongue, mouth, esophagus, and intestine, and corneal nerves, as well as skeletal deformities of the feet and chest.
In sporadic MTC, somatic RET gene mutations are described in 25–40% of cases, and somatic H-RAS and K-RAS gene mutations are also reported. Evidence indicates that, unlike germline mutations, somatic mutations are not always initiating and are largely responsible for tumor progression. Thus, other yet unknown factors may be involved in the development of this disease [2; 3].
1.3 Epidemiology of the Disease or Condition
MTC accounts for about 4–6% of all thyroid cancers. However, with the modern screening-driven increase in the incidence of differentiated thyroid cancer (mainly due to papillary microcarcinomas), the relative proportion of MTC in some countries decreases to 1–3%. In 20–25% of cases, MTC is detected as part of MEN2 syndrome; in the remaining cases, it is sporadic [4, 5].
1.4 Features of Coding the Disease or Condition
C73 – Malignant neoplasm of thyroid gland.
The diffuse C-cell system in the thyroid can be considered an independent organ in terms of origin and function. This explains the somewhat different properties of C-cell tumors. MTC and thyroid tumors arising from A and B cells share only their localization, and their similarities end there. The neuroendocrine nature of MTC is the reason for fundamentally different approaches to its diagnosis and treatment.
1.5 Classification of the disease or condition
Etiological classification
1. Sporadic MTC.
2. Genetically determined MTC:
Sipple syndrome (MEN2A), including familial MTC;
Gorlin syndrome (MEN2B).
WHO Classification of Thyroid Tumors (5th edition, 2022)
8345/3 Medullary carcinoma
8346/3 Mixed medullary-follicular carcinoma
8347/3 Mixed medullary-papillary carcinoma
TNM staging for medullary thyroid cancer, (American Joint Committee on Cancer, 8th ed., 2017) (Table 1) [6]
T – Primary tumor
Tx – Primary tumor cannot be assessed.
T0 – No evidence of primary tumor.
T1 – Tumor ≤2 cm in greatest dimension, limited to the thyroid.
T1a – Tumor ≤1 cm, limited to the thyroid.
T1b – Tumor >1 cm but ≤2 cm in diameter, limited to the thyroid.
T2 – Tumor >2 cm but <4 cm in greatest dimension, limited to the thyroid.
T3 – Tumor ≥4 cm or any tumor with extrathyroidal extension
T3a – Tumor ≥4 cm in greatest dimension, limited to the thyroid.
T3b – Tumor of any size with gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles).
T4 – Gross extrathyroidal extension
T4a – Extrathyroidal extension into surrounding tissues: subcutaneous soft tissue, larynx, trachea, esophagus, recurrent laryngeal nerve.
T4b – Extrathyroidal extension invading prevertebral fascia, mediastinal vessels, or encasing the carotid artery.
N – Regional lymph nodes
Nx – Regional lymph nodes cannot be assessed.
N0 – No regional lymph node metastasis.
N0a – One or more regional lymph nodes with cytologic or histologic confirmation of no tumor involvement.
N0b – No radiologic or clinical evidence of regional lymph node metastasis.
N1 – Regional lymph node metastasis.
N1a – Metastasis to level VI or VII (pretracheal, paratracheal, prelaryngeal/Delphian, or upper mediastinal) lymph nodes. Can be unilateral or bilateral.
N1b – Metastasis to unilateral, bilateral, or contralateral cervical (levels I, II, III, IV, or V) or retropharyngeal lymph nodes.
M – Distant metastasis
M0 – No distant metastasis.
M1 – Distant metastasis present.
Table 1. TNM stage grouping for medullary thyroid carcinoma
T | N | M | |
|---|---|---|---|
Stage I | T1 | N0 | M0 |
Stage II | T2 T3 | N0 N0 | M0 M0 |
Stage III | T1-T3 | N1a | M0 |
Stage IVA | T4a T1-T3 | N any N1b | M0 M0 |
Stage IVB | T4b | N any | M0 |
Stage IVC | T any | N any | M1 |
1.6 Clinical presentation of the disease or condition
Localized MTC is usually asymptomatic and presents as a thyroid nodule. Locally advanced forms may manifest with dysphagia, phonation disorders, or superior vena cava syndrome. Advanced forms may present with diarrhea and Cushing's syndrome associated with hypersecretion of hormonally active peptides. Bone metastases can cause bone pain and pathological fractures.
In 25% of patients with MTC, the disease is hereditary and is a component of multiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B).
MEN2A syndrome includes MTC, pheochromocytoma, hyperparathyroidism, and less commonly Hirschsprung's disease and cutaneous lichenoid amyloidosis.
MEN2B syndrome includes MTC, pheochromocytoma, marfanoid habitus, multiple neuromas of the lips, tongue, and conjunctiva, and gastrointestinal/urinary tract ganglioneuromatosis.
When MTC is combined with other components of MEN2A or MEN2B syndrome, the clinical picture includes their respective manifestations.
Sporadic medullary thyroid carcinoma (MTC) develops most commonly between 40 and 60 years of age. The frequency of regional lymph node metastasis in the central and paravascular compartments is 14% and 11% for stage T1, and 86% and 93% for stage T2, respectively. Regional metastases are present in 70% of patients with a palpable thyroid nodule, and distant metastases are present in 10%. Prognosis depends on age and stage at diagnosis. The 10-year survival rate for stages I, II, III, and IV is 100%, 93%, 71%, and 21%, respectively. The clinical course of MTC is difficult to predict, but many patients with distant metastases survive for decades. Despite active detection of MTC in recent years, the disease is diagnosed at stage III-IV in half of the patients [4].
The age of onset of hereditary MTC depends on the location of the mutation in the RET gene. With germline mutations M918T (MEN2B) and C634 (MEN2A), MTC can develop in early childhood and even in the first year of life (M918T). With other mutation locations, MTC develops at an older age [4]. Knowledge of the mutation location is the basis for preventive measures in families with hereditary MTC (see Prevention section).
2. Diagnostics, medical indications and contraindications for diagnostic methods
Diagnostic criteria:
at the preoperative stage — high blood calcitonin levels, cytological picture of thyroid cancer, high calcitonin level in needle washout fluid.
at the postoperative stage — confirmation of MTC by histological and immunohistochemical examination [4].
2.1 Complaints and Anamnesis
Most cases of MTC are detected during screening ultrasound of the thyroid and parathyroid glands, blood calcitonin testing in patients with nodular goiter or a family history of MTC, or during workup for pheochromocytoma. Advanced forms may present with complaints of neck deformity, voice change, enlarged cervical lymph nodes, or diarrhea. Distant metastases may be discovered incidentally during evaluation for other conditions.
At the pre-hospital diagnostic stage for MTC, all patients with a thyroid nodule are recommended to undergo a history taking to rule out risk factors that determine membership in the MTC risk group [6].
GGR CLOE 5Grade of Recommendation – C (Level of Evidence 5)
Comments: MTC risk factors include the presence of 1) a family or personal history of thyroid cancer or pheochromocytoma; 2) dysphagia or dysphonia; 3) enlargement of cervical lymph nodes
2.2 Physical Examination
It is recommended during physical examination to pay attention to changes in neck contours, the presence of a thyroid nodule, enlargement of regional lymph nodes, and voice changes. Attention should also be paid to symptoms of hormone production (hypercorticism, diarrhea) and clinical manifestations of other components of MEN2A and MEN2B syndromes [4].
GGR CLOE 5Grade of Recommendation – C (Level of Evidence 5)
Comments: MEN2B syndrome is characterized by a marfanoid habitus, lip thickening, and mucosal neuromas of the tongue. MEN2A syndrome may present with lichenified skin rashes [4].
2.3 Laboratory Diagnostics
To rule out MTC, patients with a thyroid nodule, pheochromocytoma, or other syndromic or physical signs of MEN2 syndrome are recommended to undergo blood calcitonin testing [6, 7].
GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)
Comments: Calcitonin is a highly sensitive and specific marker for MTC. Evaluating blood calcitonin levels as a diagnostic method for MTC significantly outperforms ultrasound and FNA in terms of sensitivity and specificity. This test can alter indications for FNA (size, calcitonin washout from the needle) and therefore should be performed at the primary stage of evaluation.
The prognostic value in diagnosing MTC depends on the serum calcitonin level. At levels >100 pg/mL, the probability of MTC approaches 100% [8]. Exceptions are rare calcitonin-secreting neuroendocrine tumors of other localizations (pancreas, lungs, etc.) [9]. Calcitonin levels above the reference range but <100 pg/mL may be a manifestation of either MTC or C-cell hyperplasia associated with other thyroid tumors and non-neoplastic conditions [9, 10]. With calcitonin levels of 50-100 pg/mL, the probability of MTC is 25-81%; with calcitonin levels of 20-50 pg/mL, the probability of MTC is 8.3-26% [8, 10].
Calcitonin concentration should be evaluated taking into account gender, age, and methodological differences in the upper limit of normal reference ranges. Calcitonin concentrations are higher in men than in women. In children under 3 years of age, calcitonin levels are higher than in older children and adults.
Fine-needle aspiration biopsy is recommended for all patients with suspected MTC as the primary method for the differential diagnosis of benign and malignant lesions of the thyroid gland and lymph nodes. In cases of moderately elevated serum calcitonin levels (<100 pg/mL), the cytological examination of the fine-needle aspiration biopsy smear of the thyroid nodule and cervical lymph nodes is recommended to be supplemented by determining calcitonin levels in the needle washout fluid [11].
GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)
Comment: The sensitivity of cytological examination of a fine-needle aspiration biopsy smear of a thyroid nodule in diagnosing MTC ranges from 20% to 86%, with an average of 54%, according to meta-analysis data [11]. Additional determination of calcitonin in the needle washout fluid increases the detection rate of MTC up to 98% [11]. However, high calcitonin levels in the washout can also occur in C-cell hyperplasia associated with other thyroid tumors and non-neoplastic conditions (hypercalcemia, hypergastrinemia, omeprazole intake, etc.). The threshold value of calcitonin in washout fluid for diagnosing MTC has not been established. Interpretation of washout calcitonin in the presence of a negative cytological conclusion and a moderately elevated serum calcitonin level (<100 pg/mL) requires expert evaluation [10]. Additional measurement of blood carcinoembryonic antigen (CEA) levels [10] and determination of calcitonin in washout fluid from puncture of normal thyroid tissue may also be useful. Extremely high calcitonin figures (over 2000 pg/mL) in washout fluid from normal tissue (outside the nodule) dramatically increase the probability of secondary C-cell hyperplasia.
The use of calcitonin-stimulation tests (with #calcium gluconate**) is recommended in the differential diagnosis between MTC and extrathyroidal calcitonin-producing tumors in patients over 18 years of age [36].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
Comment. High calcitonin values can be determined in rare calcitonin-producing neuroendocrine tumors of extrathyroidal localization: lungs, pancreas, thymus. The cells of these tumors lack calcium-sensing receptors and therefore do not respond with a release of calcitonin in response to elevated calcium during a stimulation test with #calcium gluconate** 10% (intravenous infusion of #calcium gluconate** 10% over 30 seconds at a dose of 2.5 mg/kg with blood sampling at 2, 3, and 5 minutes to determine calcitonin levels) [37].
The use of calcitonin-stimulation tests in patients with verified MTC to determine disease extent is not recommended [6].
GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)
All patients diagnosed with MTC are recommended to undergo molecular genetic testing for mutations in the RET gene from blood [6, 22].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
Comments: testing for germline RET mutations differentiates sporadic cases from hereditary forms of MTC. Detection of a germline RET mutation allows for planning further screening for pheochromocytoma and other diseases associated with MEN2A and MEN2B syndromes. Identification of a germline RET mutation is also necessary to determine the need for screening relatives of MTC patients to identify mutation carriers and provide them with timely treatment (see Prevention section).
When a germline RET mutation responsible for MEN2A/MEN2B syndrome is identified, it is recommended to undergo screening for pheochromocytoma (CT/MRI of the adrenal glands; if masses are detected, testing for metanephrines in blood or 24-hour urine) [4, 6].
GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)
When a germline RET mutation responsible for MEN2A syndrome is identified, it is recommended to measure blood ionized calcium and blood parathyroid hormone levels to detect primary hyperparathyroidism [4, 6].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
2.4 Instrumental Diagnostics
All patients with suspected MTC must undergo ultrasound of the thyroid and parathyroid glands, as well as ultrasound of the cervical lymph nodes (one anatomical region) to assess the nature of the thyroid lesion and regional lymph nodes [12, 13].
Level of Consensus CLevel of Evidence 5Level of Consensus C (Level of Evidence 5)
Comments: the TIRADS (Thyroid Imaging Reporting and Data System) scale for assessing the probability of thyroid cancer, which is accepted almost worldwide, has lower sensitivity and specificity for MTC than for differentiated thyroid cancer. Features such as solid structure, hypoechogenicity, irregular margins, and the presence of microcalcifications are less common than in papillary thyroid cancer. Some researchers have demonstrated TIRADS type II semiotics, i.e., typical benign changes (structural heterogeneity with fluid-filled areas and clear, smooth margins, i.e., a benign nodule) in 20–25% of patients with MTC. Thus, the role of ultrasound in MTC is to detect a thyroid nodule, assess the state of the cervical lymph node basin, and determine indications for FNA [12-14].
Preoperative spiral computed tomography (CT) of the neck, computed tomography of the chest, computed tomography of the abdominal organs with intravenous bolus contrast enhancement, or magnetic resonance imaging of the abdominal organs with intravenous administration of a hepatotropic contrast agent are recommended for all patients with MTC in the presence of regional lymph node metastases (N1) or with a serum calcitonin level >400 pg/ml in order to rule out distant metastases [4, 6].
GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)
PET combined with CT using tumorotropic radiopharmaceuticals (fluorine-18 fluorodeoxyglucose [18F]) and somatostatin receptor imaging are not recommended as routine methods for initial screening for MTC metastases in patients in whom FNA data and/or calcitonin levels allow the diagnosis of MTC to be established or suspected [2].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
Patients with MTC are recommended to undergo a preoperative evaluation to detect pheochromocytoma [4].
GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)
Comment: surgical treatment of MTC in undiagnosed pheochromocytoma is associated with a high risk of fatal events. Any of the following criteria may be used to rule out pheochromocytoma:
absence of pathological adrenal changes according to CT or MRI data.
negative test for RET mutation;
normal levels of free metanephrines in blood plasma or fractionated metanephrines in 24-hour urine [4, 6];
2.5 Other Procedures
It is recommended to perform pathomorphological examination of biopsy (surgical) material using immunohistochemical methods to confirm the expression of calcitonin and CEA in the tumor and the absence of thyroglobulin expression [4].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
In the case of unresectable or progressive MTC and the absence of a germline RET mutation (if tested), it is recommended to perform molecular genetic testing for mutations in the RET gene in biopsy (surgical) material [4, 6].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
Comment: If a germline RET mutation is present, testing the tumor tissue is impractical, since the tumor will, with a high degree of probability, contain the same mutation as found in the blood. Information on the presence of a RET mutation (germline or somatic) is important for selecting a drug for systemic targeted therapy in unresectable, progressive locally advanced, and metastatic MTC (see section 3.2 Medical treatment).
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1 Surgical Treatment
In resectable locoregional tumor disease, regardless of the presence/absence of distant metastases (except for symptomatic and life-threatening ones), it is recommended to perform thyroidectomy and level VI lymph node dissection (lymphadenectomy) to improve patient survival [4].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
In the presence of metastatic lesions of the lateral lymph node basin proven by FNA +/- washout for calcitonin, in addition to thyroidectomy with level VI lymph node dissection (lymphadenectomy), level II-V lymph node dissection is additionally recommended to improve patient survival [4].
Comments: If radical treatment is impossible (invasion of the esophagus, trachea, larynx), the issue of the extent of surgical treatment for the primary tumor and regional metastases is decided individually, taking into account the risk of potential complications and the prognosis of the disease [4].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
If MTC is diagnosed after hemithyroidectomy, reoperation – completion thyroidectomy with level VI lymph node dissection (lymphadenectomy) – is recommended in cases of multicentric tumor growth, positive resection margin, elevated postoperative calcitonin level in the absence of distant metastases, presence of a germline RET mutation or family history of MEN2 syndrome, or clinical signs of tumor in the residual thyroid tissue or cervical lymph nodes in order to improve patient survival [2].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
Upon detection of a resectable regional recurrence, it is recommended to perform repeat lymph node dissection (lymphadenectomy), if clinically appropriate [4, 6]
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
Comment: In one-third of patients with regional recurrence, achieving locoregional control and normalization of calcitonin is possible after repeat neck surgeries. It is preferable to perform extended lymph node dissection (lymphadenectomy) rather than excision of individual metastases, except when extended lymph node dissection (lymphadenectomy) has been performed previously [6].
Patients with MTC after thyroidectomy are recommended levothyroxine sodium** replacement therapy to maintain thyroid-stimulating hormone (TSH) within normal limits [4].
GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)
3.2 Pharmacotherapy
Patients with unresectable and/or metastatic MTC with symptoms, including carcinoid syndrome, or life-threatening conditions, as well as disease progression according to RECIST criteria [15], are recommended to receive systemic therapy [16].
GSI ALoE 2Grade of Recommendation — A (Level of Evidence — 2)
Comment: Systemic therapy is prescribed to patients with proven progression according to RECIST 1.1 criteria in cases of locally advanced unresectable and/or metastatic MTC, symptoms of compression or invasion of vital organs, or the development of paraneoplastic endocrine syndromes (diarrhea, ACTH-dependent hypercorticism). An isolated increase in calcitonin and CEA levels without confirmed metastases is not a reason for prescribing systemic therapy. It is also advisable to refrain from prescribing systemic therapy in cases of small, slowly progressive metastases and a calcitonin and CEA doubling time of >2 years.
To select the first-line systemic therapy drug for MTC, it is recommended to perform molecular genetic testing for mutations in the RET gene in postoperative (biopsy) material. If a RET gene mutation was previously detected in the blood, testing in postoperative (biopsy) material is not performed [6, 22].
Leads to CEvidence level 5Level of recommendation evidence — C (level of data reliability — 5)
Comment: Patients with progressive inoperable and/or metastatic MTC who do not have a germline RET mutation or whose RET status is unknown are recommended to have their tumor tissue tested for the presence of a RET mutation [6]. Patients with a confirmed germline RET mutation do not require additional tumor tissue testing.
If the patient has a germline or somatic mutation in the RET gene and there are indications for systemic therapy, it is recommended to prescribe the selective RET inhibitor (L01EX Other protein kinase inhibitors) selpercatinib at a dose of 160 mg twice daily for a body weight >50 kg, or 120 mg twice daily for a body weight <50 kg [6, 22].
GSI ALoE 2Grade of Recommendation — A (Level of Evidence — 2)
Comment: The phase III randomized LIBRETTO-531 trial (n=291) demonstrated the superiority of selpercatinib over vandetanib** and cabozantinib** in patients with advanced RET-mutant medullary thyroid cancer (MTC). Selpercatinib therapy reduced the risk of progression and death by 72% (HR 0.28, p<0.001). Selpercatinib showed advantages in progression-free survival at 12 months of treatment (86.8% vs. 65.7%) and objective response rate (69.4% vs. 38.8%). Selpercatinib has a better safety profile compared to vandetanib** and cabozantinib**. Dose reductions were required in 38.9% and 77.3% of patients in the selpercatinib and control groups, respectively, and therapy discontinuation occurred in 4.7% and 26.8% [22]. The most frequent adverse events were arterial hypertension (42.5%), dry mouth (31.6%), diarrhea (26.4%), and increased ALT (26.4%), with rare QT prolongation (4.7%) [22]. The efficacy of selpercatinib did not depend on prior exposure to other TKIs [21]. The drug is approved for use from 2 years of age. Administration of selpercatinib to children and young adults aged 2 to 20 years at a dose of 92 mg/m2 twice daily showed a safety and efficacy profile comparable to adults [42], which led the FDA to grant accelerated approval for the drug in pediatric patients aged 2 years and older (https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-selpercatinib-pediatric-patients-two-years-and-older-ret-altered)
In the absence of a RET mutation or if the RET status is unknown, #vandetanib** 300 mg daily orally is recommended as first-line systemic therapy until disease progression or unacceptable toxicity [16-17].
GOR ALoE 2Grade of Recommendation — A (Level of Evidence — 2)
Comment: Vandetanib is a multi-targeted kinase inhibitor of RET, VEGFR, and EGFR. In a phase III randomized trial (ZETA) in patients with unresectable, locally advanced, and metastatic MTC (n=331), vandetanib** increased progression-free survival from 19.3 to 30.5 months. No increase in overall survival was demonstrated. During treatment, blood pressure, ECG (QT interval), and renal function (creatinine, proteinuria) must be monitored. The development of cardio- and nephrotoxicity requires a dose reduction or drug discontinuation (temporary or permanent) [16–17]. In a study of children and adolescents aged 5 to 18 years, the drug at a dose of 100 mg/m2/day was well tolerated and led to a reduction in tumor size [40]
In case of MTC progression during therapy with #vandetanib** or intolerance to #vandetanib**, therapy with #cabozantinib** 60 mg daily orally is recommended until disease progression or unacceptable toxicity [18–20].
GOR ALoE 2Grade of Recommendation — A (Level of Evidence — 2)
Comment: Cabozantinib** is a multi-targeted inhibitor of RET, VEGFR2, and MET. In a phase III randomized trial (EXAM) in patients with locally advanced and metastatic MTC (n=330), cabozantinib** at a dose of 140 mg daily increased progression-free survival from 4 to 11.2 months. Dose reduction due to adverse effects was required in 79% of patients. Rare serious adverse events include bleeding, gastrointestinal (GI) perforation, and fistulas. Blood pressure, urine protein levels, creatinine, and blood electrolytes must be monitored [18–19]. Given the poor tolerability of the 140 mg/day dose, initiating treatment at 60 mg/day has been proposed. In a phase IV randomized trial (EXAMINER) in patients with progressive metastatic MTC (n=247), the efficacy of treatment at 60 mg/day was comparable to the 140 mg/day dose with lower toxicity [20]. In children, cabozantinib** has been investigated in solid tumors at a dose of 40 mg/m2/day. Toxicity after the first cycle (28 days) was noted in 19%, and late toxicity in 38% of patients [41].
In selected cases, it is recommended to use L01EX: other protein kinase inhibitors in patients older than 18 years (#sorafenib** 400 mg twice daily until progression or unacceptable toxicity to improve patient survival, #sunitinib** 50 mg once daily until progression or unacceptable toxicity to improve patient survival, #lenvatinib** 24 mg once daily until progression or unacceptable toxicity to improve patient survival, #pazopanib** 800 mg once daily until progression or unacceptable toxicity to improve patient survival) if first-line drugs are unavailable or ineffective [23-26].
GCR CLEL 4Grade of Recommendations — C (Level of Evidence — 4)
Comment: Clinical trial results have demonstrated the efficacy of #sorafenib**, #sunitinib**, #lenvatinib**, and #pazopanib** in patients with MTC [23-26]. Serious adverse effects of TKIs include bleeding, hypertension, and hepatotoxicity. The drug is prescribed only if the expected benefit outweighs the risk of complications.
In recurrent unresectable or metastatic medullary thyroid cancer progressing on standard targeted therapy regimens with a high tumor mutational burden (TMB > 10 mutations/Mb), #pembrolizumab** 200 mg IV infusion on day 1, with a cycle duration of 21 days, is recommended until progression or unacceptable toxicity to improve patient survival [6, 27].
GOR ALoE 3Grade of Recommendation — A (Level of Evidence — 3)
Comment: The efficacy of treatment with pembrolizumab** was evaluated in a phase II clinical trial (KEYNOTE-158) in patients with advanced solid tumors, including thyroid cancer. Pembrolizumab** was effective in tumors with high mutational burden (> 10 mutations/Mb) across a wide range of cancers, including thyroid cancer [27].
3.3 Other treatments
For solitary or symptomatic metastases, local treatment methods are recommended: surgical tumor removal, radiofrequency ablation (RFA), embolization, and radiation therapy to improve patients' quality of life [28-30, 39].
GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)
For metastatic bone lesions with severe pain syndrome or a risk of fractures, vertebroplasty, bone resection, RFA, and external beam radiotherapy (EBRT), including stereotactic radiotherapy, are recommended to improve patients' quality of life [4, 28].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
In case of acute spinal cord compression, systemic corticosteroids and surgical spinal stabilization are recommended to improve patients' quality of life [4].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
For patients with bone metastases, the prescription of M05BA: bisphosphonates is recommended to reduce the risk of pathological fractures [4, 35].
GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)
Comment: clinical experience with bisphosphonates # in MTC is limited. Administration of bisphosphonates can cause hypocalcemia, which must be taken into account in patients with postoperative hypoparathyroidism.
For metastatic liver lesions in the case of symptomatic metastases and inefficacy of targeted therapy, liver resection for solitary lesions or chemoembolization/embolization for solitary and multiple lesions is recommended to improve quality of life and survival [4, 29, 30, 39].
GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)
In the presence of solitary brain metastases, surgical treatment or stereotactic radiotherapy is recommended to improve patient survival [31, 32].
GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)
Systemic radionuclide therapy with Samarium-153 Sm-oxabifor in patients older than 18 years, taking into account the theranostic approach, is recommended if osteotropic radiopharmaceutical uptake is detected on bone scintigraphy or SPECT and metastatic skeletal lesions are confirmed by radiological and/or magnetic resonance imaging studies to improve the quality of life of patients with MTC [33-34].
GOR CLoE 5Grade of Recommendation — C (Level of Evidence — 5)
Systemic radionuclide therapy with Samarium-153 Sm-oxabifor is recommended for patients older than 18 years with confirmed metastatic skeletal lesions (number of lesions ≥3) for pain relief, in the absence of symptoms of spinal cord compression, with an interval of 3–6 months and a therapeutic activity of 0.5–1.0 mCi/kg [33-34].
GCP CLOE 5Grade of Recommendation – C (Level of Evidence – 5)
3.4 Pain Management
Pain management procedures and recommendations for MTC comply with the guidelines "Chronic Pain Syndrome in Adult Patients Requiring Palliative Medical Care" presented in the rubricator of clinical guidelines of the Russian Ministry of Health.
Medical Nutrition Therapy
Not applicable.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
General principles of rehabilitation for patients after surgical interventions, radiation therapy, and/or chemotherapy comply with the guidelines for head and neck malignant neoplasms presented in the rubricator of clinical guidelines of the Russian Ministry of Health "Malignant Neoplasms of the Oral Cavity".
5. Prevention and Dispensary Observation
5.1. Prevention
When a germline RET mutation is detected in a patient with medullary thyroid cancer (MTC), it is recommended to screen all first-degree relatives for this mutation to subsequently identify MTC/MEN2 syndrome [4, 6].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
Comment: Active screening of relatives for hereditary forms of MTC will help detect the disease in pathogenic variant carriers at an earlier stage and perform prophylactic thyroidectomy to prevent the development of MTC [4, 38]. This concept includes thyroidectomy in patients with no clinical manifestations of MTC, with a proven RET mutation, without thyroid nodules >5 mm in size, without abnormal lymph nodes on ultrasound, and with a basal calcitonin level <40 pg/mL. The main goal of prophylactic thyroidectomy is the prevention of metastasis. This method avoids central lymph node dissection, which is associated with a higher risk of hypoparathyroidism and recurrent laryngeal nerve injury.
Prophylactic thyroidectomy is recommended depending on the risk of aggressive MTC in the pathogenic variant carrier, which in turn depends on its localization in the RET gene. The highest risk of aggressive MTC is associated with the M918T germline mutation. A high risk of aggressive MTC is associated with the C634X and A883F mutations. Other pathogenic variants (mutations) are classified as moderate risk for aggressive MTC [4].
GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)
Carriers of the RET M918T germline mutation are recommended to undergo thyroidectomy as early as possible, within the 1st year of life [4].
GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)
Carriers of high-risk RET germline mutations for MTC (C634X and A883F) are recommended to undergo thyroidectomy at 5 years of age or earlier if calcitonin levels rise. If the calcitonin level is >40 pg/mL and/or there is a suspicion of metastasis to the cervical lymph nodes, additional lymph node dissection is recommended [4].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
Carriers of moderate-risk RET germline mutations for MTC are recommended to undergo annual examination starting from 5 years of age. Surgical treatment is performed if calcitonin levels rise or a thyroid tumor is detected [4].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
5.2. Dispensary follow-up
It is recommended to test blood levels of calcitonin and CEA 2–3 months after surgery, and then every 6–12 months [6].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
Comment: The main criterion for biochemical remission is a basal calcitonin level <10 pg/mL, and the risk of MTC recurrence is considered minimal. If biochemical remission is achieved, lifelong follow-up of patients with annual calcitonin assessment without any other topographic imaging studies is advisable.
Patients whose postoperative calcitonin levels have not normalized but are <150 pg/mL are recommended to undergo a neck ultrasound to detect structural recurrence [4].
GGR CLOE 5Grade of Recommendation – C (Level of Evidence 5)
Comment: A calcitonin level <150 pg/mL is most likely associated with residual disease in the neck. Distant metastases are possible in this situation, but at such calcitonin levels, they are solitary, usually small, and generally difficult to verify.
When postoperative calcitonin levels are >150 pg/mL, it is recommended to perform an ultrasound of the soft tissues (one anatomical zone) of the neck, contrast-enhanced chest CT, bone scintigraphy, contrast-enhanced MRI of the abdomen (contrast-enhanced liver MRI), or positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals with 18F-DOPA or 68Ga-DOTATATE to detect metastases [4, 6, 43].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
Comments: The higher the calcitonin level, the greater the likelihood of distant metastases. Performing PET-CT with tumorotropic radiopharmaceuticals such as 18F-DOPA or 68Ga-DOTATATE allows for a more accurate assessment of disease extent. These tracers have varying sensitivity for MTC metastases in different locations and can be used synchronously or metachronously.
The frequency of follow-up examinations in patients with hypercalcitoninemia depends on the dynamics of calcitonin and CEA. If calcitonin and CEA levels are stable, imaging methods (CT, MRI, PET-CT with tumorotropic radiopharmaceuticals (18F-DOPA or 68Ga-DOTATATE)) do not need to be repeated. If calcitonin or CEA levels rise, repeat imaging is indicated to confirm structural progression and determine the management strategy regarding local or systemic therapy.
Calcitonin dynamics should be assessed using the same assay method, preferably in the same laboratory, as calcitonin concentrations determined by different assays may vary significantly [4, 6].
It is recommended to measure blood TSH levels 1–2 months after surgery, and thereafter at least once a year to monitor the adequacy of levothyroxine sodium substitution therapy** [4, 6].
GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)
It is recommended to measure blood ionized calcium or total calcium, inorganic phosphorus, and parathyroid hormone levels in patients with postoperative hypoparathyroidism 1–2 months after surgery, and subsequently as clinically indicated [4, 6].
GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)
6. Organization of Medical Care
Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011, "On the Basics 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, approved by the authorized Federal Executive Authority;
2) in accordance with the procedure for the provision of medical care in the profile "oncology", mandatory for implementation throughout the Russian Federation by all medical organizations;
3) based on these clinical guidelines;
4) taking into account the standards of medical care approved by the authorized Federal Executive Authority.
Primary specialized health care is provided by an oncologist and other specialist physicians at an outpatient oncological care center or in a primary oncological office, or in the outpatient department of an oncological dispensary (oncological hospital).
If an oncological disease is suspected or detected in a patient, general practitioners, district general practitioners, general practice physicians (family physicians), specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for consultation at an outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) for the provision of primary specialized health care.
Consultation at an outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) must be performed 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 the outpatient department of the oncological dispensary (oncological hospital)) shall arrange for the acquisition of biopsy (surgical) material, as well as other diagnostic tests necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.
In the event of the impossibility of acquiring biopsy (surgical) material or performing other diagnostic tests within the medical organization that incorporates the outpatient oncological care center (primary oncological office), the attending physician shall refer the patient to an oncological dispensary (oncological hospital) or to a medical organization providing medical care to patients with oncological diseases.
The timeframe for performing pathological examinations necessary for the histological verification of malignant neoplasms shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material by the pathoanatomical bureau (department).
The timeframes for diagnostic instrumental and laboratory examinations in case of suspected oncological disease shall not exceed the timeframes established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation.
The diagnosis of an oncological disease is established by an oncologist, and in the case of malignant neoplasms of lymphoid, hematopoietic, and related tissues included in ICD-10 categories C81–C96, also by a hematologist.
An oncologist from an outpatient oncological care center (primary oncology office) refers the patient to an oncological dispensary (oncology hospital) or another medical organization providing medical care to cancer patients, including one subordinate to a federal executive body (hereinafter referred to as a federal medical organization), to clarify the diagnosis (if establishing the diagnosis is impossible, including the extent of the oncological process and disease stage), determine treatment tactics, and in the presence of medical indications for specialized, including high-tech, medical care.
For oncological diseases included in ICD-10 categories C37, C38, C40–C41, C45–C49, C58, D39, C62, C69–C70, C72, C74, as well as those corresponding to the codes of the International Classification of Diseases for Oncology (ICD-O), 3rd Edition 8936, 906-909, 8247/3, 8013/3, 8240/3, 8244/3, 8246/3, 8249/3, an oncologist at an oncological dispensary (oncological hospital) or other medical organization providing medical care to patients with oncological diseases shall organize a consultation or a medical board (consilium), including via telemedicine technologies, at federal state budgetary institutions subordinate to the Russian Ministry of Health that provide medical care (hereinafter referred to as national medical research centers for the purposes of this Procedure), in order to determine the treatment tactics.
In complex clinical cases, to clarify the diagnosis (in the event of the impossibility of establishing the diagnosis, including the extent of the oncological process and the stage of the disease) for the purpose of evaluation, interpretation, and description of the results, the oncologist shall arrange for the referral of:
digital images obtained from pathomorphological studies to the fourth-group pathologo-anatomical bureau (department) (reference center) via information interaction, including the use of teleconsultation technologies for remote interaction between medical personnel;
of digital images obtained from diagnostic imaging methods to the remote diagnostic imaging consultation center via information interaction, including the use of telemedicine technologies for remote interaction between medical workers;
biopsy (surgical) material for repeated pathomorphological, immunohistochemical, and molecular genetic studies: to the pathoanatomical bureau (department) of the fourth group (reference center), as well as to molecular genetic laboratories for molecular genetic testing.
Treatment tactics are established by a medical board (consilium) comprising oncologists, a radiation therapist, and a neurosurgeon (in cases of nervous system tumors) of the medical organization that includes departments of surgical methods for treating malignant neoplasms, antineoplastic drug therapy, and radiotherapy (hereinafter referred to as the oncological consilium), including an oncological consilium conducted using telemedicine technologies, with the involvement of other specialist physicians when necessary.
Dispensary follow-up by an oncologist for a patient with a diagnosed oncological disease is established and carried out in accordance with the procedure for dispensary observation of adults with oncological diseases.
For record-keeping purposes, information about a newly diagnosed case of an oncological disease shall be sent within 3 working days by the oncologist of the medical organization where the respective diagnosis was established to the oncological dispensary or the organization of the subject of the Russian Federation performing the function of registering patients with newly diagnosed malignant neoplasms, including via the Unified State Health Information System.
Specialized, including high-tech, medical care in medical organizations providing medical care to the adult population for oncological diseases is provided based on medical indications stipulated by the regulations on organizing the provision of specialized, including high-tech, medical care.
Specialized medical care, excluding high-tech care, in medical organizations subordinate to federal executive authorities is provided based on medical indications stipulated by paragraph 5 of the procedure for referring patients to medical organizations and other organizations subordinate to federal executive authorities for the provision of specialized (excluding high-tech) medical care, as provided in the appendix to the regulations on organizing the provision of specialized, including high-tech, medical care.
Waiting times for the provision of specialized (excluding high-tech) medical care shall not exceed the timeframes established in the program of state guarantees of free medical care to citizens, approved by the Government of the Russian Federation.
If a patient with an oncological disease has medical indications for medical rehabilitation, the oncologist arranges for it to be provided in accordance with the procedure for organizing adult medical rehabilitation.
If a patient with an oncological disease has medical indications for sanatorium-resort treatment, the oncologist arranges for it in accordance with the procedure for organizing sanatorium-resort treatment.
Palliative medical care for a patient with oncological diseases is provided in accordance with the regulations on organizing the provision of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and public associations and other non-profit organizations operating in the field of health protection.
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.
Indications for hospitalization in a medical organization in an emergency or urgent form are:
1) the presence of complications of the oncological disease requiring the provision of specialized medical care in an emergency and urgent form;
2) presence of complications of treatment (surgical intervention, RT, 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 procedures requiring subsequent monitoring in an inpatient or day-hospital setting;
2) the presence of indications for specialized antitumor treatment (surgical intervention, RT, including contact, EBRD and other types of RT, drug therapy, etc.) requiring monitoring in an inpatient 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 an inpatient or day hospital setting, provided there are no treatment complications requiring drug correction and/or medical interventions in an inpatient setting;
2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day hospital setting established by the multidisciplinary team of the medical organization providing cancer care, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting;
3) in cases of non-compliance by the patient with prescriptions or the internal regulations of the medical and prophylactic institution, provided this does not threaten the patient's life and the health of others;
4) the need to transfer the patient to another medical organization according to the relevant medical specialty profile.
The conclusion on the advisability of transferring a patient to a specialized medical organization is made after a preliminary consultation on the provided medical documents and/or a preliminary examination of the patient by specialist physicians of the medical organization to which the transfer is planned.
7. Additional Information
Factors influencing the outcome of medullary thyroid cancer:
stage of the disease at the time of MTC diagnosis;
location and number of metastases;
development of adverse events from targeted therapy.
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Performance evaluation |
|---|---|---|
1. | Serum calcitonin levels were assessed at the time of diagnosis | Yes/No |
2. | Ultrasound of the thyroid and parathyroid glands, and cervical lymph node ultrasound (one anatomical region) were performed | Yes/No |
3. | Fine-needle aspiration biopsy was performed | Yes/No |
3. | Calcitonin assay in fine-needle aspiration washout was performed in case of moderately elevated basal calcitonin levels | Yes/No |
4. | Preoperative exclusion or confirmation of pheochromocytoma was performed | Yes/No |
5. | Optimal surgical volume was selected and performed in accordance with preoperative staging | Yes/No |
6. | Blood calcium levels were checked postoperatively | Yes/No |
7. | Postoperative hormone replacement therapy was administered | Yes/No |
8. | Calcitonin and CEA levels were evaluated 2–3 months after surgery | Yes/No |
9. | Chest computed tomography, liver magnetic resonance imaging, or whole-body positron emission tomography were performed at a postoperative level of calcitonin >150 pg/mL | Yes/No |
10. | Treatment was administered with protein kinase inhibitors in accordance with indications | Yes/No |
11. | Molecular genetic testing for RET gene mutations in blood was performed | Yes/No |
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Appendix A1. Working Group Composition
Polyakov Andrey Pavlovich, MD, PhD, Associate Professor, Head of the Microsurgery Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, member of the National Association of Head and Neck Oncologists
Polkin Vyacheslav Viktorovich, PhD, Head of the Department of Radiation and Surgical Treatment of Head and Neck Diseases, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, ORCID: 0000-0003-0857-321X; eLibrary SPIN: 5604-2012; e-mail: polkin83@mail.ru.
Agababyan Tatev Artakovna, PhD, Head of the Diagnostic Radiology Department, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Email: tatevik.05@mail.ru, SPIN code: 5752-3393, AuthorID: 622660, https://orcid.org/0000-0002-9971-3451
Alymov Yury Vladimirovich, PhD, Oncologist at the Department of Surgical Treatment No. 5 (Endocrine Oncology), Clinical Oncology Research Institute named after N.N. Blokhin of the National Medical Research Center of Oncology of the Russian Ministry of Health, Executive Director of the National Association of Head and Neck Oncologists; ORCID: https://orcid.org/0000-0002-6851-9867, e-mail: allmedperevod@gmail.com.
Beltsevich Dmitry Germanovich, MD, PhD, Professor, Head of Surgical Department 1 of the Department of Surgery, National Medical Research Center for Endocrinology of the Russian Ministry of Health; ORCID: http://orcid.org/0000-0001-7098-4584, eLibrary SPIN: 4475-6327, e-mail: belts67@gmail.com.
Bolotina Larisa Vladimirovna, MD, PhD, Associate Professor of the RAS, Head of the Chemotherapy Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Ministry of Health of Russia. Chairperson of the Head and Neck Tumor Group of the Practical Guidelines of the Russian Society of Clinical Oncology, Board Member.
Borodavina Ekaterina Vladimirovna, PhD in Medical Sciences, Senior Researcher, Radiologist at the Department of Radiosurgical Treatment with Open Radionuclides, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Centre of the Ministry of Health of Russia, member of the All-Russian Public Organization "Russian Society of Head and Neck Tumors".
Vanushko Vladimir Eduardovich, MD, PhD, Professor, Head of Surgical Department 2 of the Department of Endocrine Surgery, National Medical Research Center for Endocrinology of the Russian Ministry of Health; ORCID: http://orcid.org/0000-0001-6338-7490, eLibrary SPIN: 6097-8990, e-mail: vanushko@gmail.com.
Vladimirova Lyubov Yuryevna, MD, PhD, Professor, Head of the Department of Drug Treatment of Tumors, National Medical Research Center of Oncology of the Russian Ministry of Health
Gevorkov Artem Rubenovich, PhD, Senior Researcher, Radiation Oncologist at the Department of Radiation Therapy with Modification, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, member of the National Association of Head and Neck Oncologists
Guz Alexander Olegovich, PhD, Head of the Head and Neck Tumors Department, Chelyabinsk Regional Clinical Center of Oncology and Nuclear Medicine, member of the National Association of Head and Neck Oncologists.
Gulidov Igor Alexandrovich, MD, PhD, Professor, Head of the Radiation Therapy Department, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health
Ignatova Anastasia Valeryevna, PhD, Oncologist at the Department of Surgical Treatment No. 5 (Endocrine Oncology), Clinical Oncology Research Institute named after N.N. Blokhin of the National Medical Research Center of Oncology of the Russian Ministry of Health, member of the National Association of Head and Neck Oncologists, Assistant at the Department of General and Clinical Dentistry, Peoples' Friendship University of Russia (RUDN University). ORCID: https://orcid.org/0000-0002-6796-0968
Ilyin Alexey Amurovich, MD, PhD, Leading Researcher at the Department of Radiation and Surgical Treatment of Head and Neck Diseases, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health
Isaev Pavel Anatolyevich, MD, PhD, Leading Researcher at the Department of Radiation and Surgical Treatment of Head and Neck Diseases, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health
Kostromina Ekaterina Viktorovna, PhD, Senior Researcher at the Scientific Department of Diagnostic and Interventional Radiology, N.P. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Associate Professor of the Department of Academic and Methodological Work, Associate Professor of the Department of Radiology and Biomedical Imaging, Faculty of Postgraduate Education, North-State Medical University, Radiologist at the Diagnostic Radiology Department, N.P. Petrov National Medical Research Center of Oncology.
Kropotov Mikhail Alekseevich, MD, PhD, Head of the Head and Neck Tumors Department, National Medical Research Center of Oncology of the Russian Ministry of Health
Krylov Valery Vasilyevich, MD, PhD, Head of the Department of Radiosurgical Treatment with Unsealed Nuclides, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
Kulbakin Denis Evgenyevich, MD, PhD, Senior Researcher, Highest Category Physician at the Head and Neck Tumors Department, Cancer Research Institute of the Tomsk National Research Medical Center.
Kutukova Svetlana Igorevna, MD, Professor at the Department of Dentistry and Maxillofacial Surgery, Associate Professor at the Department of Oncology of the Faculty of Postgraduate Education at Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation, Oncologist at Department No. 10 (Antineoplastic Drug Therapy) at City Clinical Oncology Dispensary of Saint Petersburg.
Melnichenko Galina Afanasyevna, MD, PhD, Professor, Academician of the Russian Academy of Sciences, Deputy Director, National Medical Research Center for Endocrinology of the Russian Ministry of Health; ORCID: http://orcid.org/0000-0002-5634-7877, eLibrary SPIN: 8615-0038, e-mail: teofrast2000@mail.ru.
Mudunov Ali Muradovich, MD, PhD, Professor of the Russian Academy of Sciences, Head of the Head and Neck Tumors Department, Lapino Medical Center, President of the National Association of Head and Neck Oncologists.
Musin Shamil Ismagilovich, PhD, Head of the Head and Neck Tumors Department, Republican Clinical Oncology Dispensary of the Ministry of Health of the Republic of Bashkortostan
Nikiforovich Petr Alekseevich, Deputy Chief Physician for Oncological Service Coordination at the National Medical Research Center for Endocrinology of the Ministry of Health of Russia.
Podvyaznikov Sergey Olegovich, MD, PhD, Professor, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Vice President of the National Association of Head and Neck Oncologists.
Radzhabova Zamira Akhmedovna, PhD, Head of the Head and Neck Surgical Department, N.P. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, member of the National Association of Head and Neck Oncologists
Reshetov Igor Vladimirovich, MD, PhD, Academician of the Russian Academy of Sciences, Head of the Department of Oncology, Radiotherapy and Reconstructive Surgery, I.M. Sechenov First Moscow State Medical University, President of the Federation of Specialists in the Treatment of Head and Neck Diseases
Romanov Ilya Stanislavovich, MD, PhD, Senior Researcher at the Department of Surgical Treatment No. 5 (Endocrine Oncology), Clinical Oncology Research Institute named after N.N. Blokhin of the National Medical Research Center of Oncology of the Russian Ministry of Health, member of the National Association of Head and Neck Oncologists. ORCID: https://orcid.org/0000-0002-5421-5985
Romashchenko Pavel Nikolaevich, MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department and Clinic of Faculty Surgery named after S.P. Fedorov, S.M. Kirov Military Medical Academy of the Ministry of Defense of the Russian Federation.
Natalia A. Rubtsova, Dr. of Sci. (Med.), Head of the Radiology Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health. Chief Freelance Specialist in Radiation and Instrumental Diagnostics of the Russian Ministry of Health in the Central Federal District of the Russian Federation.
Rudyk Andrey Nikolaevich, PhD, Assistant at the Department of Oncology, Radiology and Palliative Medicine, Kazan State Medical Academy, Oncologist at the Head and Neck Tumors Department, Prof. M.Z. Sigal Republican Clinical Oncology Dispensary of the Republic of Tatarstan
Rumyantsev Pavel Olegovich, MD, PhD, Deputy Chief Physician, Chief Oncologist-Radiologist, SOGAZ International Medical Center, member of the National Association of Head and Neck Oncologists; ORCID: http://orcid.org/0000-0002-7721-634X, eLibrary SPIN: 7085-7976, e-mail: pavelrum@gmail.com.
Severskaya, Natalia V., Cand. of Sci. (Med.), Head of the Clinical Laboratory Diagnostics Department, Endocrinologist at the A.F. Tsyb MRRC, a branch of the National Medical Research Radiological Center of the Russian Ministry of Health, ORCID: 0000-0002-9426-8459, eLibrary SPIN: 3999-8816, e-mail: severskn@mrrc.obninsk.ru
Semiglazova, Tatiana Yu., Dr. of Sci. (Med.), Associate Professor, Head of the Scientific Department of Innovative Methods of Therapeutic Oncology and Rehabilitation at the N.N. Petrov National Medical Research Center of Oncology
Sleptsov, Ilya V., Dr. of Sci. (Med.), Professor at the Department of Surgery with a Course of Surgical Endocrinology at the Institute of Medical Education, Deputy Director for Medical Affairs; ORCID: 0000-0002-1903-5081; eLibrary SPIN: 2481-4331; e-mail: newsurgery@yandex.ru.
Stepanova, Alexandra M., Head of the Rehabilitation Department at the P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Radiological Center of the Russian Ministry of Health
Falaleeva, Natalia A., Dr. of Sci. (Med.), Head of the Department of Drug Treatment of Malignant Neoplasms at the A.F. Tsyb MRRC, a branch of the National Medical Research Radiological Center of the Russian Ministry of Health
Khmelevsky, Evgeny V., Dr. of Sci. (Med.), Professor, Head of the Radiotherapy Department at the P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Radiation Oncologist at the P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Radiological Center of the Russian Ministry of Health
Chernikov, Roman A., Dr. of Sci. (Med.), Head of the Department of Endocrinology and Endocrine Surgery at the Pirogov Clinic of High Medical Technologies, Saint Petersburg State University; ORCID: 0000-0002-3001-664X; eLibrary SPIN code: 7093-1088; e-mail: yaddd@yandex.ru.
Choynzonov, Evgeny L., Dr. of Sci. (Med.), Academician of the Russian Academy of Sciences, Director of the Cancer Research Institute of the Tomsk National Research Medical Center, Head of the Head and Neck Tumors Department at the Cancer Research Institute of the Tomsk National Research Medical Center, Head of the Department of Oncology at the Siberian State Medical University of the Russian Ministry of Health, Member of the All-Russian Public Organization "Russian Society of Head and Neck Cancer Specialists"
Shurinov Andrey Yuryevich, PhD in Medical Sciences, Senior Researcher at the Department of Radiosurgical Treatment with Open Radionuclides, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health
Healthcare Delivery Organization Section
Gevorkyan, Tigran G., Deputy Director at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health
Ivanov, Sergey A., Dr. of Sci. (Med.), Professor of the Russian Academy of Sciences, Director of the A.F. Tsyb MRRC – a branch of the National Medical Research Radiological Center of the Russian Ministry of Health
Nevolskikh, Alexey A., Dr. of Sci. (Med.), Deputy Director for Clinical Work at the A.F. Tsyb MRRC – a branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
Khaylova, Zhanna V., Cand. of Sci. (Med.), Deputy Director for Organizational and Methodological Work at the A.F. Tsyb MRRC, a branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
Conflict of interest:
The authors declare no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
Oncologist;
Surgeon;
Endocrinologist;
Radiologist;
Radiation oncologist;
General practitioner (family physician);
Pathologist.
Table 2. Scale for grading levels of evidence (LE) for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized clinical trials with meta-analysis |
2 | Individual studies with reference-method control, or individual randomized controlled trials and systematic reviews of studies of any design except randomized controlled trials incorporating meta-analysis |
3 | Studies without sequential reference-standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 3. Levels of Evidence (LOE) for preventive, therapeutic, and rehabilitative methods (interventions)
LoE | Definition |
|---|---|
1 | Systematic review of randomized controlled trials with meta-analysis |
2 | Individual randomized clinical trials and systematic reviews of studies of any design, excluding randomized clinical trials, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 4. Scale for grading recommendation strengths (SRS) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines
The clinical practice guidelines update mechanism provides for their systematic review at least once every 3 years, as well as upon the emergence of new evidence-based medicine data on diagnosis, treatment, prevention, and rehabilitation, or in the presence of justified additions/comments to previously approved guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
No information available
Appendix B. Physician Action Algorithms
Appendix C. Patient Information
When a hereditary mutation is detected in medullary thyroid cancer, molecular genetic testing is performed not only on the patient, but also on their blood relatives (children, siblings, parents);
When planning pregnancy, patients with suspected and/or proven familial medullary thyroid cancer should consult a geneticist.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Not applicable.