Biliary Tract Cancer: Clinical Guidelines

List of Abbreviations

AJCC – American Joint Committee on Cancer

DCR – Disease control rate

ECOG – The Eastern Cooperative Oncology Group

EGFR – Epidermal growth factor receptor

HR – Hazard ratio

MSI-H – Microsatellite instability-high

OR – Odds ratio

PD-L1 – Programmed cell death 1-ligand 1

RR – Risk ratio

AFP – Alpha-fetoprotein

PFS – Progression-free survival

HCC – Hepatocellular carcinoma

CI – Confidence interval

CT – Computed Tomography

RT – Radiation therapy

MRI – Magnetic resonance imaging

MRCP – Magnetic resonance cholangiopancreatography

OS – Overall survival

PET-CT – Positron emission tomography-computed tomography

GBC – Gallbladder cancer

RFA – Radiofrequency ablation

CEA – Carcinoembryonic antigen

TACE – Transarterial chemoembolization

Ultrasound – Ultrasound Investigation

USCT – Ultrasound computed tomography

CT – Computed tomography

PDT – Photodynamic therapy

CRT – Chemoradiotherapy

Terms and Definitions

Biliary tract cancer (biliary tract tumors) is a neoplastic lesion of the gallbladder and bile ducts.

Cholangiocarcinoma is a malignant tumor originating from the bile duct epithelium. Cholangiocarcinomas are subdivided by anatomical location into intrahepatic and extrahepatic.

Depending on the level of the lesion, extrahepatic cholangiocarcinomas of the proximal and distal bile ducts are distinguished in clinical practice.

Proximal extrahepatic cholangiocarcinoma (Klatskin tumor, perihilar cholangiocarcinoma) is a neoplastic lesion of the lobular and common hepatic ducts, localized proximally from the junction of the common hepatic and cystic ducts up to the origin of the second-order segmental hepatic ducts.

Distal extrahepatic cholangiocarcinoma – a neoplastic lesion of the common bile duct, localized proximally from the ampulla of Vater to the junction of the common hepatic and cystic ducts.

Gallbladder cancer (GBC) is a malignant tumor originating from the gallbladder epithelium; it is the most common of all biliary tract cancers.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition (group of diseases or conditions)

Biliary tract cancer is a group of tumors developing from the epithelium of the gallbladder and bile ducts. Among patients with biliary cancer, one-third of cases are bile duct tumors (cholangiocarcinomas), and two-thirds are gallbladder tumors.

Gallbladder cancer (GBC) is a malignant tumor originating from the gallbladder epithelium; it is the most common of all biliary tract cancers. GBC is characterized by local and vascular invasion, extensive regional lymphogenic and hematogenous metastasis.

Bile duct cancer (cholangiocarcinoma) is a malignant tumor originating from the bile duct epithelium.

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

Risk factors for GBC include conditions associated with chronic inflammation, including cholelithiasis. Other risk factors include: gallbladder polyps greater than 1 cm in diameter, chronic infections, sclerosing cholangitis, gallbladder adenomatosis. Inflammatory bowel disease (ulcerative colitis) is also associated with an increased risk of biliary tract cancer [1–3].

Conditions preceding the development of CC: sclerosing autoimmune cholangitis, chronic infectious cholangitis, Caroli disease, chronic helminthic infection (Opisthorchis viverrini, Clonorchis sinensis, and Opisthorchis felineus). Cholelithiasis is not associated with the etiology of cholangiocarcinoma. Potential risk factors for the development of cholangiocarcinomas include inflammatory bowel diseases, as well as hepatitis B or C infection, liver cirrhosis, diabetes mellitus, obesity, alcohol abuse, non-alcoholic fatty liver disease, and smoking [4–6].

1.3 Epidemiology of the Disease or Condition (Groups of Diseases or Conditions)

Biliary tract cancer – cholangiocellular cancer, gallbladder cancer, and bile duct cancer – is a rare malignant tumor. In morbidity and mortality statistics, these tumors are assessed jointly. In the Russian Federation in 2018, 8,810 patients were diagnosed with liver cancer. By rough estimates, intrahepatic bile duct cancer accounts for about 10% of this number, i.e., in 2018, about 880 patients were registered with intrahepatic bile duct cancer in Russia. Extrahepatic cholangiocarcinomas and gallbladder cancer were diagnosed in 3,713 primary patients (1,424 men and 2,289 women). Exact mortality statistics for biliary cancer in Russia are absent. Nevertheless, 10,018 patients died from liver cancer (hepatocellular and cholangiocellular carcinomas), and 3,819 patients died from gallbladder cancer, extrahepatic bile duct cancer, and other unspecified digestive organs. Incidence increases with age, and women develop CC more frequently than men [7,8].

1.4 Specifics of coding the disease or condition (group of diseases or conditions) according to the International Statistical Classification of Diseases and Related Health Problems

C22.1 Intrahepatic bile duct cancer

C23 Gallbladder cancer

C24.0 Extrahepatic bile duct cancer

Epithelial tumors (biliary)

a) Benign

8202/0 Bile duct adenoma (peribiliary hamartoma and others)

8202/0 Microcystic adenoma

9013/0 Biliary adenofibroma

b) Precancerous neoplasms

8148/2 Biliary intraepithelial neoplasia, grade 3 (BiIN-3)

8503/0 Intraductal papillary neoplasm with low-to-moderate intraepithelial neoplasia

8503/2 Intraductal papillary neoplasm with high-grade intraepithelial neoplasia

8470/0 Mucinous cystic neoplasm with low-to-moderate intraepithelial neoplasia

8470/2 Mucinous cystic neoplasm with high-grade intraepithelial neoplasia

Malignant neoplasms

8160/3 Intrahepatic cholangiocarcinoma

8503/3 Intraductal papillary neoplasm with invasive carcinoma

8470/3 Mucinous cystic neoplasm with invasive carcinoma

Extrahepatic bile ducts and gallbladder

Epithelial tumors

Precancerous neoplasms

8140/0 Adenoma

8211/0 Tubular

8260/0 Papillary

8263/0 Tubulopapillary

8148/2 Biliary intraepithelial neoplasia, grade 3 (BiIN-3)

8503/0 Intracholecystic (gallbladder) or intraductal (bile ducts) papillary neoplasm with low-to-moderate intraepithelial neoplasia

8503/2 Intracholecystic (gallbladder) or intraductal (bile ducts) papillary neoplasm with high-grade intraepithelial neoplasia

8470/0 Mucinous cystic neoplasm with low-to-moderate intraepithelial neoplasia

8470/2 Mucinous cystic neoplasm with high-grade intraepithelial neoplasia

Malignant neoplasms (cancer)

8140/3 Adenocarcinoma

8140/3 Adenocarcinoma, biliary type

8140/3 Adenocarcinoma, gastric foveolar type

8144/3 Adenocarcinoma, intestinal type

8310/3 Clear cell adenocarcinoma

8480/3 Mucinous adenocarcinoma

8490/3 Signet-ring cell carcinoma

8560/3 Adenosquamous carcinoma

8503/3 Intracholecystic (gallbladder) or intraductal (bile ducts) papillary neoplasm with invasive carcinoma

8470/3 Mucinous cystic neoplasm with invasive carcinoma

8070/3 Squamous cell carcinoma

8020/3 Undifferentiated carcinoma

1.5 Classification of the disease or condition (groups of diseases or conditions)

Biliary tract cancer is a group of neoplasms originating from the epithelium of the gallbladder and bile ducts. Among patients with biliary tract cancer, one-third of cases are bile duct tumors (cholangiocarcinomas) and two-thirds are gallbladder tumors.

Cholangiocarcinomas are classified into intrahepatic and extrahepatic. The latter include carcinoma of the common bile duct and perihilar bile duct tumors (Klatskin tumor). Extrahepatic bile duct cancer is significantly more common: Klatskin tumors account for 50% of cholangiocarcinomas, distal tumors for 42%, and intrahepatic involvement occurs in 8% of cases [10]. Among gallbladder tumors, adenocarcinomas are the most common (80%), while other variants are also possible: squamous cell, anaplastic, small cell carcinoma, lymphomas, sarcomas [1]. More than 90% of cholangiocarcinoma cases are adenocarcinomas, frequently (>80%) mucinous. Based on their growth pattern, biliary adenocarcinomas are divided into three types:

• sclerosing (scirrhous) – most commonly develops in the extrahepatic bile ducts, characterized by diagnostic difficulty and low resectability,

• nodular – more commonly develops in an intrahepatic location, characterized by high invasive properties and low resectability,

• papillary – characterized by early manifestation and high resectability.

1.6 Clinical presentation of the disease or condition (groups of diseases or conditions)

Early symptoms of intrahepatic cholangiocarcinoma and gallbladder cancer are extremely nonspecific: discomfort, a feeling of heaviness in the right upper quadrant or epigastrium, and decreased appetite. Sometimes manifestations can be detected through changes in biochemical blood tests (increased transaminase activity or cholestasis markers), as well as elevated tumor marker levels in high-risk groups (cholelithiasis, gallbladder polyps, primary sclerosing cholangitis, parasitic infestation), which, however, is also nonspecific.

More significant symptoms (upper abdominal pain, nausea, vomiting, loss of appetite or even food aversion, weight loss, jaundice, pruritus, fever, hepatomegaly and enlargement of the gallbladder, ascites) are signs of advanced stages of the disease. Symptoms of biliary cancer may be masked by the symptoms of underlying conditions (cholelithiasis, primary sclerosing cholangitis, ulcerative colitis).

Extrahepatic bile duct cancer, conversely, frequently presents with obstructive jaundice due to obstruction of the common hepatic/common bile duct or associated with bilateral blockade of the right and left hepatic ducts. Prior to complete obstruction with a full-blown presentation of obstructive jaundice, there may be nonspecific complaints of heaviness in the right upper quadrant, fever, chills, followed by pruritus, pale stools, and dark urine. At the preclinical or subclinical level, abnormalities in biochemical blood tests (cytolysis and cholestasis markers) are possible.

Abdominal ultrasound as a screening method can detect a liver mass in intrahepatic cholangiocarcinoma, an infiltrate in the gallbladder area or growth of a previously identified polyp in gallbladder cancer, as well as signs of biliary hypertension in extrahepatic bile duct cancer or complicated forms of gallbladder cancer/intrahepatic cholangiocarcinoma.

TNM Staging 8th Edition

Gallbladder Cancer Staging (8th Edition)

T – Primary tumor:

T_X – Primary tumor cannot be assessed;

T₀ – No evidence of primary tumor;

Tis – Carcinoma in situ;

T₁ – Tumor invades lamina propria or muscle layer;

T_1a – Tumor invades lamina propria;

T_1b – Tumor invades muscle layer;

T₂ – Tumor invades perimuscular connective tissue on the peritoneal side without involvement of the serosa (visceral peritoneum) or tumor invades perimuscular connective tissue on the hepatic side without extension into the liver;

T_2a – Tumor invades perimuscular connective tissue on the peritoneal side without involvement of the serosa (visceral peritoneum);

T_2b – Tumor invades perimuscular connective tissue on the hepatic side without extension into the liver;

T₃ – Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or other adjacent organs and structures (stomach, duodenum, colon, pancreas, omentum, extrahepatic bile ducts);

T₄ – Tumor invades the portal vein or hepatic artery, or invades two or more adjacent organs and structures.

N – Regional lymph nodes:

N_X – Regional lymph nodes cannot be assessed;

N₀ – No regional lymph node metastasis;

N₁ – Metastases in 1 to 3 regional lymph nodes;

N₂ – Metastases in 4 or more regional lymph nodes.

M – Distant metastasis:

M₀ – No distant metastasis;

M₁ – Distant metastasis present.

Table 1. Gallbladder cancer stage grouping.

Histological grade:

G_x – Grade cannot be assessed;

G₁ – Well differentiated;

G₂ – Moderately differentiated;

G₃ – Poorly differentiated.

Staging of intrahepatic cholangiocarcinoma

T – Primary tumor:

T_x – primary tumor cannot be assessed;

T₀ – no evidence of primary tumor;

Tis – carcinoma in situ (intraductal tumor);

T₁ – solitary tumor without vascular invasion, <5 cm or >5 cm;

T_1a – solitary tumor <5 cm without vascular invasion;

T_1b – solitary tumor >5 cm without vascular invasion;

T₂ – solitary tumor with intrahepatic vascular invasion, or multiple tumors with or without vascular invasion;

T₃ – tumor perforating the visceral peritoneum;

T₄ – tumor with direct invasion of local structures.

N – Regional lymph nodes:

N_x – regional lymph nodes cannot be assessed;

N₀ – No regional lymph node metastasis;

N₁ – regional lymph node metastases present.

M – Distant metastasis:

M₀ – no distant metastasis;

M₁ – distant metastases present.

Table 2. Stage grouping for intrahepatic cholangiocarcinoma.

Histological grade

G_x – grade cannot be assessed;

G₁ – well-differentiated;

G₂ – Moderately differentiated;

G₃ – poorly differentiated.

Staging of extrahepatic cholangiocarcinoma (perihilar)

T – Primary tumor:

T_X – Primary tumor cannot be assessed;

T₀ – No evidence of primary tumor;

Tis – carcinoma in situ (high-grade dysplasia);

T₁ – tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue;

T₂ – tumor invades beyond the bile duct wall into surrounding adipose tissue, or tumor invades adjacent hepatic parenchyma;

T_2a – tumor invades beyond the duct wall into surrounding adipose tissue;

T_2b – tumor invades adjacent hepatic parenchyma;

T₃ – tumor invades unilateral branches of the portal vein or hepatic artery;

T₄ – tumor invades the main portal vein or its branches bilaterally, or the common hepatic artery, or involves second-order biliary ducts bilaterally; or unilateral second-order duct involvement with contralateral portal vein and hepatic artery invasion. Hepatic artery and portal veins, N₁, N₂ lymph nodes.

N – Regional lymph nodes:

N_X – regional lymph node involvement cannot be assessed;

N₀ – No regional lymph node metastasis;

N₁ – one to three positive lymph nodes, involving nodes along the cystic duct, common bile duct, hepatic artery, posterior pancreatoduodenal and/or portal vein;

N₂ – four or more positive lymph nodes from the sites described for N_1.

M – Distant metastasis:

M₀ – No distant metastasis;

M₁ – Distant metastasis present.

Table 3. Stage grouping for extrahepatic cholangiocarcinoma (perihilar).

Histological grade:

G_x – Grade cannot be assessed;

G₁ – Well differentiated;

G₂ – Moderately differentiated;

G₃ – poorly differentiated.

The modified Bismuth-Corlette staging system classifies proximal bile duct tumors into 4 types based on the extent of bile duct involvement (Table 4).

Table 4. Bismuth-Corlette classification (for proximal cholangiocarcinoma).

Staging of extrahepatic cholangiocarcinoma (distal – below the cystic duct insertion)

T – Primary tumor:

T_X – Primary tumor cannot be assessed;

T₀ – No evidence of primary tumor;

Tis – carcinoma in situ (high-grade dysplasia);

T₁ – tumor invades the duct wall to a depth of less than 5 mm;

T₂ – tumor invades the duct wall to a depth of 5–12 mm;

T₃ – tumor invades the duct wall to a depth of more than 12 mm;

T₄ – tumor invasion of the celiac trunk, superior mesenteric artery, or common hepatic artery.

N – Regional lymph nodes:

N_X – regional lymph node involvement cannot be assessed;

N₀ – No regional lymph node metastasis;

N₁ – one to three positive lymph nodes;

N₂ – four or more positive lymph nodes.

M – Distant metastasis:

M₀ – No distant metastasis;

M₁ – Distant metastasis present.

Table 5. Stage grouping for distal extrahepatic cholangiocarcinoma.

Histological grade:

G_x – Grade cannot be assessed;

G₁ – Well differentiated;

G₂ – Moderately differentiated;

G₃ – poorly differentiated.

1.1 Definition of the disease or condition

Biliary tract cancer – encompasses a group of malignancies arising from the epithelium of the gallbladder and bile ducts. Less than one-third of biliary tract cancers are gallbladder tumors, while the remainder are intrahepatic and extrahepatic cholangiocarcinomas. Tumors of the ampulla of Vater are excluded from biliary tract tumors.

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

Potential risk factors for the development of intrahepatic cholangiocarcinoma include inflammatory bowel disease, chronic viral hepatitis B or C, liver cirrhosis, diabetes mellitus, obesity, alcohol use, non-alcoholic fatty liver disease, and smoking [4–6].

Conditions predisposing to the development of extrahepatic cholangiocarcinoma: autoimmune sclerosing cholangitis, chronic infectious cholangitis, Caroli disease, chronic helminthiasis (Opisthorchis viverrini, Clonorchis sinensis, and Opisthorchis felineus). Cholelithiasis is not associated with the etiology of cholangiocarcinoma.

Risk factors for gallbladder cancer include conditions associated with chronic inflammation, including cholelithiasis. Other risk factors include gallbladder polyps greater than 1 cm in diameter, chronic infections, sclerosing cholangitis, and adenomyomatosis of the gallbladder. Inflammatory bowel disease (ulcerative colitis) is also associated with an increased risk of biliary tract cancer [1–3].

1.3 Epidemiology of the Disease or Condition

Biliary tract cancer – a rare type of malignant tumor. In most morbidity and mortality reports, tumors are not categorized by the specific site of the bile ducts and are analyzed as a single group. In the Russian Federation in 2020, there were 8,957 patients diagnosed with liver cancer. Rough estimates indicate that intrahepatic cholangiocarcinoma accounts for approximately 10% of this total, meaning about 896 new cases of intrahepatic cholangiocarcinoma were registered in Russia in 2020. Extrahepatic cholangiocarcinoma and gallbladder cancer were diagnosed in 3,539 primary patients (1,295 males and 2,244 females). Precise mortality statistics for biliary tract cancer in Russia are unavailable. However, 10,625 patients died from liver cancer (hepatocellular and cholangiocarcinomas), and 3,783 patients died from gallbladder cancer, extrahepatic cholangiocarcinoma, and other ill-defined digestive organs. Incidence increases with age; intrahepatic cholangiocarcinoma is diagnosed more frequently in women than in men [7,8].

Diagnosis and treatment of children with these malignant neoplasms are carried out in accordance with guidelines for patients over 18 years of age (due to the low number of pediatric cases) within national (federal) centers.

1.4 Features of Coding the Disease or Condition

C22.1 Intrahepatic cholangiocarcinoma

C23 Malignant neoplasm of gallbladder

C24.0 Extrahepatic bile duct

Bile duct or passage, NOS

Common bile duct

Cystic duct

Hepatic duct

C24.8 Lesion of biliary tract overlapping one and more above subcategories

Malignant neoplasm of biliary tract overlapping one or more of the above sites, malignant neoplasm involving intrahepatic and extrahepatic bile ducts, malignant neoplasm of biliary tract whose point of origin cannot be classified to any of the categories C22.1-C24.8

C24.9 Biliary tract lesion, unspecified

1.5 Classification of the disease or condition

World Health Organization, 2019

Tumors of the liver and intrahepatic bile ducts

Benign biliary tumors and precancerous lesions

8160/0 – Bile duct adenoma (biliary adenoma)

9013/0 – Adenofibroma, NOS

8148/0 – Biliary intraepithelial neoplasia, low grade

8148/2 – Biliary intraepithelial neoplasia, high grade

8503/0 – Intraductal papillary neoplasm with intraepithelial neoplasia, low grade

8503/2 – Intraductal papillary neoplasm with intraepithelial neoplasia, high grade

8503/3 – Intraductal papillary neoplasm with associated invasive carcinoma

8470/0 – Mucinous cystic neoplasm with intraepithelial neoplasia, low grade

8470/2 – Mucinous cystic neoplasm with intraepithelial neoplasia, high grade

8470/3 – Mucinous cystic neoplasm with associated invasive carcinoma

Malignant biliary tumors

8160/3 – Cholangiocarcinoma

Large duct intrahepatic cholangiocarcinoma

Small duct intrahepatic cholangiocarcinoma

8020/3 – Carcinoma, undifferentiated, NOS

8180/3 – Combined hepatocellular carcinoma and cholangiocarcinoma

8240/3 – Neuroendocrine tumor, NOS

8240/3 – Neuroendocrine tumor, grade 1

8249/3 – Neuroendocrine tumor, grade 2

8249/3 – Neuroendocrine tumor, grade 3

8246/3 – Neuroendocrine carcinoma, NOS

8013/3 – Large cell neuroendocrine carcinoma

8041/3 – Small cell neuroendocrine carcinoma

8154/3 – Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN)

Tumors of extrahepatic bile ducts

8160/3 – Cholangiocarcinoma

8070/3 – Squamous cell carcinoma, NOS

8560/3 – Adenosquamous carcinoma

8020/3 – Undifferentiated carcinoma, NOS

Tumors of the gallbladder

8140/3 – Adenocarcinoma, NOS

8070/3 – Squamous cell carcinoma, NOS

8020/3 – Carcinoma, undifferentiated, NOS

Extrahepatic bile duct cancer is significantly more common than intrahepatic cholangiocarcinoma: tumors of the proximal extrahepatic bile ducts account for 50% of cholangiocarcinomas, distal tumors account for 42%, and intrahepatic lesions occur in 8% of cases [9]. Among gallbladder tumors, adenocarcinomas are the most frequent (80%), although other variants may occur, including squamous cell, anaplastic, small cell carcinoma, lymphomas, and sarcomas [1]. Gallbladder cancer is characterized by local and vascular invasion, extensive regional lymphogenic, and hematogenous metastasis. More than 90% of cholangiocarcinomas are adenocarcinomas, frequently (>80%) mucinous. Previously, tumors were macroscopically classified into 4 types based on their growth pattern [167]:

• Infiltrative

• Nodular

• Nodular-infiltrative

• Papillary

1.6 Clinical presentation of the disease or condition

Early symptoms of intrahepatic bile duct cancer and gallbladder cancer are extremely nonspecific: discomfort, a feeling of heaviness in the right upper quadrant or epigastrium, and decreased appetite. Sometimes a tumor lesion can be detected through changes in blood biochemistry results (elevated transaminases or cholestasis markers) as well as elevated tumor marker levels in high-risk patients (cholelithiasis, gallbladder polyps, primary sclerosing cholangitis, parasitic infestation, etc.), which, however, is also nonspecific.

More significant symptoms (upper abdominal pain, nausea, vomiting, loss of appetite or even food aversion, weight loss, jaundice, pruritus, fever, hepatomegaly and enlargement of the gallbladder, ascites) are signs of advanced stages of the disease. Symptoms of biliary cancer may be masked by the symptoms of underlying conditions (cholelithiasis, primary sclerosing cholangitis, ulcerative colitis).

Extrahepatic bile duct cancer, conversely, often presents with obstructive jaundice due to obstruction of the common hepatic/bile duct or in connection with a bilateral block of the right and left hepatic ducts. Prior to complete obstruction with a full clinical picture of obstructive jaundice, there may be nonspecific complaints of heaviness in the upper quadrant, fever, chills, followed by pruritus, pale stools, and dark urine. At the preclinical or subclinical level, abnormalities in blood chemistry (markers of cytolysis, cholestasis) are possible.

TNM Staging (8th Edition)

Staging of intrahepatic bile duct tumors

T – Primary tumor:

T_x – primary tumor cannot be assessed;

T₀ – no evidence of primary tumor;

T_is – carcinoma in situ (intraductal tumor);

T₁ – solitary tumor without vascular invasion, <5 cm or >5 cm;

T_1a – solitary tumor <5 cm without vascular invasion;

T_1b – solitary tumor >5 cm without vascular invasion;

T₂ – solitary tumor with intrahepatic vascular invasion or multiple tumor nodules, with or without vascular invasion;

T₃ – tumor perforating the visceral peritoneum;

T₄ – tumor involving extrahepatic local structures via direct invasion.

N – Regional lymph nodes

N_x – regional lymph nodes cannot be assessed;

N₀ – No regional lymph node metastasis;

N₁ – regional lymph node metastases present.

M – Distant metastasis:

M₀ – no distant metastasis;

M₁ – distant metastases present.

Regional lymph nodes for intrahepatic cholangiocarcinoma of the left lobe of the liver include nodes along the hepatoduodenal ligament (nodes along the common bile duct, hepatic artery, portal vein, and cystic duct), lymph nodes along the hepatogastric ligament, and inferior diaphragmatic nodes (as a variant of metastasis).

For tumors of the right lobe of the liver, regional lymph nodes include those along the hepatoduodenal ligament, as well as juxtaduodenal and peripancreatic lymph nodes.

Table 1.

AJCC staging grouping for intrahepatic cholangiocarcinoma

For all intrahepatic cholangiocarcinomas, metastasis to the celiac, para-aortic, or paracaval lymph nodes is considered distant. Typical sites of distant spread include intrahepatic lesions, peritoneal involvement, and—in descending order of frequency—bones, lungs, and pleura.

Histological grading:

G_x – Grade cannot be assessed;

G₁ – well-differentiated;

G₂ – Moderately differentiated;

G₃ – poorly differentiated.

AJCC staging of proximal extrahepatic bile duct cancer

T – Primary tumor:

T_X – Primary tumor cannot be assessed;

T₀ – no primary tumor found;

T_is – carcinoma in situ (high-grade dysplasia);

T₁ – tumor confined to the bile duct, with extension up to the muscular layer or fibrous tissue;

T₂ – tumor invades beyond the bile duct wall into surrounding adipose tissue, or tumor invades the adjacent hepatic parenchyma:

T_2a – tumor invades beyond the duct wall into surrounding adipose tissue;

T_2b – tumor invades adjacent hepatic parenchyma;

T₃ – tumor invades unilateral branches of the portal vein or hepatic artery;

T₄ – tumor invades the main portal vein trunk or its branches bilaterally; or invasion of the common hepatic artery; or tumor extension to second-order biliary ducts bilaterally; or involvement of second-order ducts on one side with invasion of the contralateral portal vein branch or involvement of the hepatic artery.

N – regional lymph nodes: the hepatic hilum, along the cystic and common bile ducts, portal vein, hepatic artery, as well as posterior pancreatoduodenal lymph nodes.

N_X – regional lymph node involvement cannot be assessed;

N₀ – No regional lymph node metastasis;

N₁ – one to three positive lymph nodes, involving nodes along the cystic duct, common bile duct, hepatic artery, posterior pancreatoduodenal and/or portal vein;

N₂ – four or more positive lymph nodes from the sites described for N₁.

M – Distant metastasis:

M₀ – No distant metastasis;

M₁ – Distant metastasis present.

Lymph node metastases located distal to the hepatoduodenal ligament are classified as distant metastases.

Table 2.

AJCC staging grouping for extrahepatic cholangiocarcinoma (perihilar)

Histological grading:

Gx – grade cannot be assessed;

G1 – well differentiated;

G2 – moderately differentiated;

G3 – poorly differentiated.

The modified Bismuth-Corlette staging system classifies proximal bile duct tumors into 4 types based on the extent of biliary duct involvement (Table 3).

Table 3.

Bismuth-Corlette classification (for proximal cholangiocarcinoma)

Staging of distal extrahepatic cholangiocarcinoma

T – Primary tumor:

T_X – Primary tumor cannot be assessed;

T₀ – No evidence of primary tumor;

T_is – carcinoma in situ (high-grade dysplasia).

T₁ – tumor invades the duct wall to a depth of less than 5 mm;

T₂ – tumor invades the duct wall to a depth of 5–12 mm;

T₃ – tumor invades the duct wall to a depth of more than 12 mm;

T₄ – tumor invasion of the celiac trunk, superior mesenteric artery, and/or common hepatic artery.

N – regional lymph nodes: along the common bile duct, common hepatic artery, portal vein, anterior and posterior pancreatoduodenal nodes, and lymph nodes located to the right and along the superior mesenteric artery.

N_X – regional lymph node involvement cannot be assessed;

N₀ – No regional lymph node metastasis;

N₁ – one to three positive lymph nodes;

N₂ – four or more positive lymph nodes.

M – Distant metastasis:

M₀ – No distant metastasis;

M₁ – Distant metastasis present.

Table 4.

Staging grouping for extrahepatic cholangiocarcinoma (distal)

Histological grading:

G_x – Grade cannot be assessed;

G₁ – Well differentiated;

G₂ – Moderately differentiated;

G₃ – poorly differentiated.

Gallbladder cancer staging

T – Primary tumor:

T_X – Primary tumor cannot be assessed;

T₀ – No evidence of primary tumor;

Tis – carcinoma in situ;

T₁ – Tumor invades lamina propria or muscle layer;

T_1a – Tumor invades lamina propria;

T_1b – Tumor invades muscle layer;

T₂ – tumor invades the perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum), or tumor invades the perimuscular connective tissue on the hepatic side, without extension into the liver.

T_2a – tumor invades the perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum).

T_2b – tumor invades the perimuscular connective tissue on the hepatic side, without extension into the liver.

T₃ – tumor perforates the serosa (visceral peritoneum) and/or direct invasion into the liver and/or other adjacent organs and structures (stomach, duodenum, colon, pancreas, omentum, extrahepatic bile ducts);

T₄ – Tumor invades the portal vein or hepatic artery, or invades two or more adjacent organs and structures.

N – regional lymph nodes include those along the hepatoduodenal ligament, as well as periduodenal and peripancreatic lymph nodes.

N_X – Regional lymph nodes cannot be assessed;

N₀ – No regional lymph node metastasis;

N₁ – Metastases in 1 to 3 regional lymph nodes;

N₂ – Metastases in 4 or more regional lymph nodes.

M – Distant metastasis:

M₀ – No distant metastasis;

M₁ – Distant metastasis present.

Table 5 Gallbladder cancer stage grouping

Histological grading:

Gx – grade cannot be assessed;

G1 – well differentiated;

G2 – moderately differentiated;

G3 – poorly differentiated.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria:

1. Presence of a liver tumor lesion according to ultrasound, MRI, or CT data.

2. Morphological confirmation of the diagnosis.

3. Exclusion of other primary tumor sites (colon cancer, gastric cancer, etc.)

2.1 Complaints and Anamnesis

Comment: gathering information on complaints and detailed history, including family history, is performed to identify factors that may influence treatment choices

2.2 Physical Examination

2.3 Laboratory Diagnostics

• For patients with intrahepatic cholangiocarcinoma, it is recommended to determine ABO blood groups and Rh factor (D antigen); molecular biological blood testing for Hepatitis B virus; molecular biological blood testing for Hepatitis C virus; complete blood count (CBC) with differential, general clinical and routine biochemical blood tests, blood levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), alpha-fetoprotein (AFP), IgG4, coagulation profile (screening hemostasis test), as well as urinalysis to determine treatment strategy and differential diagnosis [10, 19–24].

Level of Evidence BGrade of Recommendation 4Level of Evidence – B (Grade of Recommendation 4)

Comment: this scope of laboratory testing is performed at the diagnostic stage and prior to treatment planning. During therapy, the scope and frequency of laboratory tests are determined by clinical necessity. A complete blood count must be performed no more than 5 days before starting a course of chemotherapy or radiation therapy. The list of biochemical blood parameters and coagulation tests should be determined by the attending physician for each patient individually, taking into account their characteristics. It should be borne in mind that CA 19-9 levels can be elevated in the presence of jaundice, cholangitis, or other inflammatory processes in the pancreatobiliary region; therefore, baseline CA 19-9 testing should be performed after biliary decompression, normalization of bilirubin levels, and resolution of inflammation.

Extrahepatic cholangiocarcinoma (proximal and distal extrahepatic bile duct cancer)

Comment: determining AFP levels in a patient with suspected extrahepatic cholangiocarcinoma is optional.

Gallbladder cancer

Comment: determining AFP levels when a patient is suspected of having gallbladder cancer is optional.

2.4 Instrumental Diagnostics

Intrahepatic cholangiocarcinoma

• Comprehensive abdominal ultrasound as a screening method can detect a liver mass in the intrahepatic form of cholangiocarcinoma; it can also be used for navigation during percutaneous aspiration/incisional biopsy of soft tissue tumors and tumor-like lesions [168], and for monitoring the efficacy of medical treatment.

Comment: A negative biopsy result in the presence of positive imaging findings is an indication for repeated procedures until diagnostically significant material is obtained. The optimal method for tissue acquisition is percutaneous transhepatic core needle biopsy under ultrasound or CT guidance; liver biopsy under endovideochirurgical guidance is also acceptable. Open liver biopsy should be reserved for exceptionally rare cases.

Differential diagnosis: Key neoplasms to differentiate from intrahepatic ICC while ruling out metastatic disease in the liver include hepatocellular carcinoma, epithelioid hemangioendothelioma, biliary adenoma, ductular reaction with atypia, and biliary adenofibroma. Each of these nosological entities has a characteristic histological pattern. Immunohistochemical (IHC) staining is typically used to clarify the diagnosis [3, 164].

• When tumor pathology is detected on ultrasound, it is recommended to perform contrast-enhanced computed tomography (CT) of the abdominal cavity, contrast-enhanced CT of the pelvic organs in women/men, and/or contrast-enhanced magnetic resonance imaging (MRI) of the abdominal cavity with magnetic resonance cholangiopancreatography (MRCP) [10, 29, 30]. MRI has an advantage over CT in assessing the intrahepatic spread of cholangiocarcinoma [171].

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

Comment: CT is more specific than ultrasound for detecting lymph node involvement, organ invasion, and distant metastases; MRI can be used to differentiate between benign tumors and cancer [31].

• Before initiating treatment, all patients are recommended to undergo chest CT to determine the extent of the tumor process [10, 32, 33].

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

• When planning surgical treatment, adult patients are recommended to undergo positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals (PET-CT) to rule out distant metastases if they are suspected based on comprehensive workup data [36, 37].

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

Extrahepatic cholangiocarcinoma (cancer of the proximal and distal extrahepatic bile ducts)

Abdominal ultrasound has limited value during the initial diagnosis of patients with extrahepatic cholangiocarcinoma. In the vast majority of cases, tumor pathology can only be suspected based on indirect signs (dilation of the intra- and extrahepatic bile ducts, occasionally thickening of the duct walls, and in some cases lymphadenopathy in the lesser omentum projection).

• Prior to treatment, all patients who are candidates for non-surgical therapies are recommended to have morphological confirmation of the diagnosis with pathomorphological examination of biopsy (surgical) material using immunohistochemical methods [10, 40–42]. In cases of technical difficulties and complication risks associated with biopsy acquisition, cytological confirmation of the diagnosis is acceptable. Biopsy can be performed percutaneously under ultrasound or CT guidance for nodular tumor growth patterns; in other cases, intraductal biopsy is used (via antegrade or retrograde access, depending on the prior or ongoing biliary decompression method) under fluoroscopic and/or video-cholangioscopic guidance.

GOR CLOE 5Grade of Recommendation — C (Level of Evidence — 5)

Comment: biopsy is necessary for prescribing conservative treatment regimens, but is not mandatory when planning surgical intervention in cases of a clear clinical and instrumental presentation [40, 43].

• All patients with extrahepatic cholangiocarcinoma are recommended to undergo contrast-enhanced computed tomography (CT) of the abdomen and pelvis and/or contrast-enhanced magnetic resonance imaging (MRI) of the abdomen with magnetic resonance cholangiography [10, 29, 30]. When a tumor process of the distal extrahepatic bile ducts is suspected, MSCT is the primary diagnostic method. When proximal bile duct involvement is suspected, MRI and magnetic resonance cholangiopancreatography (MRCP) must be performed. Contrast-enhanced MSCT in this case serves as a staging and refinement diagnostic modality. The definitive method for determining the level of biliary obstruction is direct cholangiography (ERCP or PTC), which is currently used solely at the time of biliary decompression and immediately prior to surgery [137–142].

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

Comment: CT is more specific than ultrasound for detecting lymph node involvement, organ invasion, and distant metastases; MRI can be used to differentiate between benign tumors and cancer [31]. In cancer of the proximal extrahepatic bile ducts, MRI and MRCP are performed to clarify the degree of separation of the intrahepatic bile ducts and to identify tumor spread. Contrast-enhanced MSCT is performed when involvement of the vessels of the hepatopancreatoduodenal zone is suspected.

• Before initiating treatment, all patients are recommended to undergo chest CT to determine the extent of the tumor process [10, 32, 33].

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

• When planning surgical treatment in adults, it is recommended to perform positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals (PET-CT) to rule out distant metastases if there is suspicion of their presence based on comprehensive workup data [36, 37].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1)

• When planning surgical treatment in adults, it is recommended to perform diagnostic laparoscopy to rule out distant metastases in cases where their presence is suspected based on comprehensive workup data [2, 3, 38].

GoR ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

• Patients with cancer of the distal extrahepatic bile ducts are recommended to undergo endoscopic ultrasonography of the pancreatobiliary zone for further assessment of local tumor extent and differential diagnosis with tumor involvement of the pancreatic head [195, 198].

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

Gallbladder cancer

• Abdominal ultrasound is recommended during the initial diagnosis of patients with suspected gallbladder cancer and is of great importance for screening. It can detect an infiltrate in the gallbladder region or the growth of a previously identified polyp, as well as signs of biliary hypertension in complicated cases [196, 197].

GPP CLoE 5Grade of Recommendation – C (Level of Evidence – 5).

Comment: Morphological verification of the disease is extremely difficult in the early stages and in most cases only becomes possible when the tumor process extends into the liver parenchyma or fills the gallbladder lumen with tumor masses [188, 189]. Biopsy is necessary for prescribing conservative treatment regimens, but is not mandatory when planning surgical intervention in cases of a clear clinical and instrumental presentation[40, 43].

• All patients with gallbladder cancer are recommended to undergo contrast-enhanced computed tomography of the abdomen and contrast-enhanced computed tomography of the pelvis, and/or contrast-enhanced magnetic resonance imaging of the abdomen, and contrast-enhanced magnetic resonance imaging of the retroperitoneal space with magnetic resonance cholangiopancreatography to determine treatment strategy [10, 29, 30].

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

Comment: if imaging findings raise suspicion of tumor invasion into the stomach and/or colon, the patient must undergo esophagogastroduodenoscopy and colonoscopy.

• Before initiating treatment, all patients are recommended to undergo chest CT to determine the extent of the tumor process [10, 32, 33].

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

• When planning surgical treatment, it is recommended to perform positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals to rule out distant metastases if their presence is suspected based on comprehensive examination data [36,37].

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

• When planning surgical treatment, it is recommended to perform diagnostic laparoscopy to rule out distant metastases if their presence is suspected based on comprehensive examination data [2,3,38].

GRR BLOE 2Level of Recommendations Assurance – B (Level of Evidence - 2)

Comment: Due to the high frequency of peritoneal dissemination in patients with gallbladder cancer, this method helps avoid unjustified laparotomy in one-third of patients who appear resectable based on MRI/CT/PET-CT results[2,39].

2.5 Other Procedures

The majority of intrahepatic cholangiocarcinomas are moderately to highly differentiated tubular adenocarcinomas [1]. Recently [2], CCA has been subdivided into 2 types based on tumor localization and immunohistochemical features:

a) biliary type with prominent expression of S100P, TFF1, AGR2; KRAS mutation is detected in 23% of cases;

b) cholangiolar type with prominent expression of N-cadherin; KRAS mutation is detected in only 1% of cases.

Intrahepatic CCAs have an immunohistochemical profile similar to other tumors of the pancreatobiliary zone and upper gastrointestinal tract. Currently, there is no single definitive stain to confirm CCA [3]. Typically, these tumors are positive for cytokeratins 7 and 19 (90%) and mucin 1 (73.8%) [162].

Focal expression of cytokeratin 20 in tumor cells is possible, but in combination with the expression of cytokeratins 7 and 19, other gastrointestinal tumors must be ruled out [1].

The most common variants of these tumors include high- and moderately differentiated biliary-type adenocarcinomas. Most of them are immunopositive for carcinoembryonic antigen, mucins 1 and 2, p53, and cytokeratin 7.

The IHC pattern of cholangiolar-type adenocarcinomas is distinct and characterized by the expression of mucin 2, carcinoembryonic antigen, and cytokeratin 20 [162].

• It is recommended to perform molecular genetic testing of a tumor tissue sample (biopsy or surgical specimen) using preferably next-generation panel sequencing (DNA/RNA) to determine the medical treatment strategy [10, 41, 44, 172]:

• molecular genetic testing for KRAS gene mutations in biopsy (surgical) material

• molecular genetic testing for BRAF gene mutations in biopsy (surgical) material

• determination of ERBB2 (HER2/Neu) gene amplification by fluorescence in situ hybridization (FISH)

• determination of mutations in MLH1, MSH2, MSH6, PMS2 genes by immunohistochemistry

Level of Evidence CGrade of Evidence 5 Level of Evidence – C (Grade of Evidence – 5)

Comment: when an activating and targetable mutation (an active drug exists that effectively targets this molecular alteration) is detected in the tumor of a patient with advanced/metastatic disease, targeted therapy based on the identified molecular aberration can significantly increase overall survival; activating mutations that determine tumor sensitivity to targeted therapy are most frequently detected (in up to 40% of cases) in intrahepatic cholangiocarcinoma. Currently, testing for NTRK and FGFR1-4 gene translocations is not included in the nomenclature of medical services; however, performing this molecular genetic testing for patients with intrahepatic cholangiocarcinoma with the aim of potentially prescribing molecularly targeted therapy is mandatory.

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

3.1 Preoperative treatment

• In the presence of obstructive jaundice, it is recommended to perform preoperative biliary decompression (percutaneous transhepatic cholangiostomy, endoscopic nasobiliary drainage, retrograde stenting) to relieve obstructive jaundice [51–53]. In clinical practice, the type of drainage should be chosen based on the level of the biliary obstruction, the goal of drainage (for subsequent surgical or palliative treatment), the technical capabilities of the clinic, and the experience of the staff [143].

GCR CLEL 2Grade of Recommendation – C (Level of Evidence – 2)

• For Bismuth type I and II obstruction in patients with proximal extrahepatic bile duct cancer, it is recommended to prioritize the endoscopic retrograde approach for biliary decompression, provided the medical institution is adequately equipped and has experienced specialists in interventional endoscopy [190].

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

• For Bismuth type III–IV obstruction in patients with proximal extrahepatic bile duct cancer and intrahepatic cholangiocarcinoma complicated by obstructive jaundice, fluoroscopically guided percutaneous external drainage of the intrahepatic bile ducts is recommended as the preferred method of biliary decompression [190, 191].

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

Comment: in patients with proximal extrahepatic cholangiocarcinoma and intrahepatic cholangiocarcinoma whose disease is complicated by obstructive jaundice, adequate drainage of both liver lobes is necessary to relieve cholangitis and prepare for radical surgery; retrograde drainage methods cannot provide this [144, 145].

• The method of choice for biliary decompression in tumor lesions of the distal extrahepatic bile ducts is endoscopic nasobiliary drainage or retrograde stent placement [146, 147]. Placement of self-expanding metal stents prior to radical surgery is unacceptable and should only be performed if unresectability of the tumor process is confirmed [163]. If endoscopic retrograde interventions are not feasible, percutaneous transhepatic cholangiostomy should be preferred [148, 149].

• When the anticipated future liver remnant volume is <40%, selective endovascular embolization of portal vein branches (typically the right branch, sometimes combined with embolization of segment IV branches) is recommended as preoperative preparation for adult patients with intrahepatic cholangiocarcinoma or proximal extrahepatic cholangiocarcinoma, which helps reduce the risk of postoperative liver failure [47–50].

  Level of Recommendation – B (Level of Evidence – 2)

Comment: preoperative portal vein embolization increases the volume of the anticipated liver remnant. Surgical treatment is performed once the target future liver remnant volume (≥ 40%) is achieved; the dynamics of its increase are evaluated no earlier than 3–5 weeks after embolization.

3.2 Surgical Treatment

3.2.1. Intrahepatic cholangiocarcinoma

• In adult patients with resectable intrahepatic cholangiocarcinoma, radical surgery involving liver resection combined with regional lymph node dissection is recommended. The goal of surgical treatment is to remove the tumor node with negative resection margins. In case of extrahepatic bile duct invasion, their resection with subsequent reconstruction is indicated [70].

LoR CLoE 4Level of Recommendation – C (Level of Evidence – 4)

Comment: The primary condition to be met when planning liver resection is the preservation of adequate blood supply, venous outflow, and bile drainage in the future liver remnant. The volume of the anticipated liver remnant should be at least 25% (of non-affected parenchyma) in the absence of laboratory and instrumental signs of cirrhosis, and at least 40% in their presence. Furthermore, in the presence of cirrhosis, the degree of impaired hepatocellular function (liver resection is advisable in patients corresponding to Child-Pugh class A) and the severity of portal hypertension (clinically significant manifestations: presence of esophageal varices, thrombocytopenia less than 100x10⁹/L) must be taken into account.

In specialized centers (equipped with appropriate personnel and facilities), liver resections may be performed using minimally invasive approaches under video-endoscopic control. Subcapsular lesions and nodules located in the lateral sectors of the liver are preferred when planning this approach [75].

It should be noted that a large tumor size and/or multiple intrahepatic lesions, invasion of major vessels or adjacent organs, and metastatic involvement of regional lymph nodes are not absolute contraindications to liver resection, although surgical outcomes in such cases are predictably worse [72].

• For local recurrence of intrahepatic cholangiocarcinoma, it is recommended to perform a repeat liver resection if preoperative examination results indicate a high likelihood of achieving a negative resection margin [73,74].

GPP ALOE 2Grading of Recommendations Assessment, Development and Evaluation (GRADE) – A (Level of Evidence 2)

Comment: repeat liver resection in patients following intrahepatic cholangiocarcinoma recurrence is associated with a statistically significant increase in 1-, 3-, and 5-year overall survival (OS): the odds ratios (OR) with 95% confidence intervals (CI) were 2.70 (1.28–5.68), 2.89 (1.15–7.27), and 5.91 (1.59–21.90), respectively[73].

• In adult patients with intrahepatic cholangiocarcinoma, liver transplantation is routinely not recommended due to the high probability of early disease progression [76–78].

GPP BLOE 2Grading of Recommendations Assessment, Development and Evaluation (GRADE) – B (Level of Evidence 2)

Comment: For intrahepatic cholangiocarcinoma, liver transplantation may be considered as a treatment option in patients with advanced cirrhosis and early-stage tumors, as well as in selected patients with multifocal liver disease following neoadjuvant therapy [79]. This approach has been associated with longer disease-free survival, but did not affect OS. Patients with very early-stage intrahepatic cholangiocarcinoma (single lesion ≤ 2 cm) who underwent liver transplantation showed a higher 5-year disease-free survival rate (67%, 95% CI 47–86%) compared to those with advanced disease (34%, 95% CI 23–46%) [79].

3.2.2. Cancer of the Proximal Extrahepatic Bile Ducts

• Surgical treatment is recommended for resectable cancer of the proximal extrahepatic bile ducts. The scope of the procedure is determined by the local extent of the tumor. In most cases, it is necessary to perform an extended right- or left-sided hemihepatectomy with resection of the tumor-involved bile ducts and segment 1 (S1) of the liver, followed by hepaticojejunostomy. A mandatory condition during surgery is frozen-section intraoperative examination of the extrahepatic bile duct resection margins to achieve a histologically negative result. Isolated resection of the extrahepatic bile ducts is possible for Bismuth type I-II tumors [45,80,81, 192, 193].

GPR BLOE 3Grade of Recommendations — B (Level of Evidence 3)

Comment: in case of portal vein invasion, its resection followed by reconstruction is advisable. [82,83]

3.2.3. Cancer of the Distal Extrahepatic Bile Ducts

• For common bile duct cancer, it is recommended to perform radical surgery in the volume of pancreatoduodenectomy with regional lymph node dissection en bloc, with frozen-section intraoperative histological examination of the duct resection margin, followed by anastomosis creation [45].

GPP CLOE 3Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 3)

Comment: in cases of tumor involvement of the suprapancreatic common bile duct (without involvement of the pancreatic head), the radical surgical volume also consists of resection of the affected bile ducts with regional lymph node dissection, provided that a negative resection margin is confirmed by frozen-section intraoperative histological examination.

3.2.4. Gallbladder Cancer

• For T_1a stage gallbladder cancer, it is recommended to perform a cholecystectomy [57].

GPP BLOE 3Grading of Recommendations Assessment, Development and Evaluation (GRADE) – B (Level of Evidence 3).

• For resectable gallbladder cancer, it is recommended to perform an extended cholecystectomy with resection of liver segments IV–V, removal of soft tissue and regional lymph nodes, with or without bile duct resection depending on their involvement in the tumor process [58–64].

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

Comment: contraindications for surgical treatment include: multiple liver metastases, ascites, peritoneal metastases, tumor involvement of the tubular structures of the hepatoduodenal ligament, occlusion of major vessels, poor general condition of the patient, and tumor involvement of the pancreatic head or duodenum.

• For gallbladder cancer with muscular layer invasion (stage I, T_1b-2N₀M₀) detected after cholecystectomy for cholecystitis, in order to improve long-term treatment outcomes, it is recommended to perform a timely repeat operation consisting of liver resection (gallbladder bed) combined with lymph node dissection and resection of the cystic duct stump, after ruling out signs of unresectability based on diagnostic imaging [46,66,68–71].

GPP BLOE 3Grading of Recommendations Assessment, Development and Evaluation (GRADE) – B (Level of Evidence 3)

Comment: if a video-endoscopic approach was used during the initial surgery, and the tumor invades the serserosa (visceral peritoneum) and/or direct liver invasion is detected, soft tissue resection along the port sites used for gallbladder extraction should be considered due to the high risk of port-site metastasis. For early-stage (pT1a) gallbladder cancer detected post-cholecystectomy, repeat surgery is not required [69].

3.3 Chemotherapy

Comment: following radical surgical treatment, monotherapy with #capecitabine** (8 cycles) is recommended regardless of lymph node involvement and tumor differentiation grade. (

Table 6).

According to meta-analysis data, adjuvant chemotherapy following both radical (R0) and margin-positive (R1) resection was associated with a statistically significant increase in OS by an average of 4.3 months (95% CI 0.88–7.79; p = 0.014) and a 41% reduction in the risk of death [hazard ratio (HR) = 0.59; 95% CI 0.49–0.71; p < 0.001][85].

According to the BILCAP study (eight 3-week cycles of #capecitabine** chemotherapy vs. observation), median OS was significantly increased in the adjuvant chemotherapy group [53 months vs. 36 months; HR 0.75, 95% CI 0.58–0.97, P = 0.028], which was also confirmed after adjusting for significant prognostic factors (lymph node status, grade, and sex) (HR 0.71, 95% CI 0.55–0.92, P = 0.010). Furthermore, intention-to-treat (ITT) analysis demonstrated higher recurrence-free survival with #capecitabine** during the first 24 months.

According to earlier meta-analyses, adjuvant chemotherapy after both radical (R0) and margin-positive (R1) resection was associated with a statistically significant increase in OS by an average of 4.3 months (95% CI 0.88–7.79; p = 0.014) and a 41% reduction in the risk of death [hazard ratio (HR) = 0.59; 95% CI 0.49–0.71; p < 0.001] [85].

There is no evidence of efficacy for adjuvant chemotherapy in biliary tract cancer when using GEMOX regimens (PRODIGE-12 trial) [150] and gemcitabine** monotherapy (BCAT trial) [151].

Following non-radical surgery (R1/R2) or in the presence of lymph node metastases, repeat resection may be performed; systemic chemotherapy (according to principles of metastatic disease treatment) and chemoradiotherapy (CRT) with pyrimidine analogues (L01BC) are also required.

It is strongly recommended to administer postoperative radiotherapy (RT) using 3D conformal RT or intensity-modulated radiation therapy. The radiation field should include the tumor bed and regional lymph node stations. Radiotherapy is delivered at a fractional dose (FD) of 2 Gy to a cumulative dose (CD) of 46 Gy, and in cases of R1/R2 resection margins, up to 50–60 Gy to the tumor bed. Following chemoradiotherapy, monotherapy with #capecitabine** is indicated (in cases of low tumor differentiation grade and/or lymph node metastases, combination regimens of gemcitabine**/#cisplatin**, #gemcitabine**/#capecitabine**)[93–94].

• In cases of local recurrence of biliary tract cancer after radical surgery, it is recommended to consider local treatment options to increase patient survival (repeat hepatic resection, local ablation techniques, or hepatic artery chemoembolization for isolated liver involvement following surgery for intrahepatic cholangiocarcinoma, photodynamic therapy, or intraductal RT for extrahepatic bile duct cancer recurrence) [73,74,91,95,96].

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

• For adult patients with unresectable localized intrahepatic CC (stages IIIa–IVa, T_3–4N_0–1M₀), it is recommended to consider loco-regional treatments (local ablation [RFA, cryoablation], transarterial chemoembolization [TACE], selective intrahepatic arterial chemotherapy, stereotactic body radiation therapy using a 3–5 day fractionation schedule to a CD of 30–50 Gy), which may be used in selected patients when the options of other primary treatments are exhausted, though they are not recommended for routine use [97–103].

GCR CLoE 4Grade of Recommendations — C (Level of Evidence — 4).

Comment: for T_3–4, RFA is not indicated.

• For adult patients with localized intraductal and periductal-infiltrative bile duct involvement (stages IIIa–IVa, T_3–4N₀M₀), it is recommended to consider intraductal photodynamic therapy (PDT) to improve bile drainage and enhance patients' quality of life (palliative care) [104,105].

GCR CLoE 4Grade of Recommendations — C (Level of Evidence — 4).

Comment: PDT involves the relatively selective accumulation of a chemical agent (photosensitizer [L01XD: Sensitizers used in photodynamic/radiation therapy]) by pathological tissue, followed by activation of the accumulated photosensitizer with light, which triggers a cascade of intracellular reactions known as the photodynamic effect, leading to tumor cell death; it improves overall survival in patients with intraductal unresectable cholangiocarcinoma and common bile duct cancer [104,105].

• In advanced stages of extrahepatic cholangiocarcinoma (stages IIIa–IVa, T_3–4N_0–1M₀) in adults, chemoradiotherapy may be recommended for symptom control related to local tumor extension [106].

GCR CLoE 4Grade of Recommendations — C (Level of Evidence — 4).

Comment: prior to radiotherapy, the administration of #gemcitabine** at a dose of 1000 mg/m2 on days 1 and 8 of the cycle in combination with capecitabine at a dose of 1500 mg/m2 on days 1 through 14, every 21 days for 4 cycles, followed by concurrent capecitabine** at a dose of 1330 mg/m2 daily (concurrent with radiotherapy) may be recommended [183, 184]. Radiotherapy is delivered as stereotactic irradiation in 3–5 fractions to a CD of 30–50 Gy. Concurrent use of gemcitabine with radiotherapy is not recommended due to limited experience and high treatment toxicity.

• In adults with disseminated biliary tract cancer (stage IVb, M1) and a satisfactory general condition, it is recommended to consider systemic chemotherapy with gemcitabine** combined with platinum derivatives +/- immunotherapy, including fluoropyrimidine-based regimens (L01BC: Pyrimidine analogues). A combination of immunotherapy and chemotherapy is recommended as a first-line treatment option for adult patients with advanced unresectable or metastatic biliary tract cancer. The addition of durvalumab** to gemcitabine** + #cisplatin**, and #pembrolizumab** to gemcitabine** + #cisplatin** significantly increases patient survival. Drug dosages are listed in Table 6 [19,107–114, 122, 173].

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

Comments: according to a double-blind, placebo-controlled phase III trial (n=685 patients) with previously untreated unresectable or metastatic biliary tract cancer, the addition of durvalumab** to gemcitabine** + #cisplatin** resulted in a significant improvement in treatment efficacy. Median overall survival (OS) in the durvalumab** and placebo groups was 12.8 (95% CI = 11.1–14.0) and 11.5 (95% CI = 10.1–12.5) months, respectively, and the hazard ratio (HR) for OS was 0.80 (95% CI = 0.66–0.97, p = 0.021). The 24-month OS rate was 24.9% (95% CI = 17.9–32.5) for patients receiving durvalumab** and 10.4% (95% CI = 4.7–18.8) for those receiving placebo. Median progression-free survival (PFS) in the durvalumab** and placebo groups was 7.2 (95% CI = 6.7–7.4) and 5.7 (95% CI = 5.6–6.7) months, and the HR for PFS was 0.75 (95% CI = 0.63–0.89, p = 0.001). The objective response rate (ORR) reached 26.7% in those receiving gemcitabine** + #cisplatin** + durvalumab**, compared to only 18.7% in the control group. The addition of durvalumab** to gemcitabine** + #cisplatin** did not worsen treatment tolerability and safety: grade 3 and 4 adverse events occurred in 75.7% of patients receiving durvalumab** and 77.8% of patients receiving placebo [122].

According to a double-blind, placebo-controlled phase III trial involving 1,069 patients with previously untreated unresectable or metastatic biliary tract cancer, the addition of pembrolizumab** to gemcitabine** + #cisplatin** resulted in a significant improvement in OS. The combination of pembrolizumab** and gemcitabine** + #cisplatin** improved overall survival (p = 0.0034). Median OS was 12.7 months in the pembrolizumab group and 10.9 months in the placebo group. The 12-month overall survival rate was 52% versus 44%, and the 24-month survival rate was 25% versus 18%, respectively [173].

Chemotherapy in the presence of drainage tubes and stents in the biliary tree is frequently (>50% of patients) complicated by acute cholangitis exacerbation, cholestasis, and cholestatic hepatitis. To prevent infectious complications (cholangitis), active monitoring of drainage patency, timely replacement of drainage tubes, and prophylactic flushing of drains with antibacterial solutions are necessary. If infection is suspected, timely broad-spectrum antibacterial therapy (J01: Antibacterials for systemic use) should be initiated, adjusted as necessary based on bacterial culture results and antibiotic susceptibility testing of the microbial flora (J01: Antibacterials for systemic use). Treatment duration is determined by tolerability, impact on the patient's quality of life, and immediate efficacy; there is no evidence of additional benefit from treatment lasting longer than 6 months. #Oxaliplatin** at a dose of 100 mg/m² IV on day 1, repeated every 3 weeks, may replace #cisplatin** combined with gemcitabine** 1000 mg/m2 in case of impaired renal function, high toxicity of cisplatin**, or other contraindications to cisplatin** [154]. Gemcitabine** + #cisplatin** chemotherapy is feasible in patients with moderately elevated bilirubin levels due to intrahepatic cholestasis, provided there is adequate bile drainage [155].

• In patients over 18 years of age with primarily unresectable locally advanced biliary tract cancer who respond effectively to loco-regional and/or systemic chemotherapy and experience a reduction in local tumor extent meeting resectability criteria due to tumor shrinkage, it is advisable for an interdisciplinary team to re-evaluate the possibility of radical surgical treatment [115, 119, 120, 156].

GCR CLoE 4Grade of Recommendations — C (Level of Evidence — 4).

Comments: The ABC-06 trial confirmed a moderate increase in OS with chemotherapy (FOLFOX) compared to active supportive care (HR 0.69).

Second-line treatment usingfluorouracila** and#irinotecana** (FOLFIRI) also broughtsomebenefit to patients. A randomized phase II trial comparing mFOLFOX and mFOLFIRI in patients with locally advanced or metastatic biliary tract cancer previously treated withgemcitabine** + #cisplatin**demonstrated similar efficacy between the two regimens [174]. Median OS and PFS were 6.3 months (95% CI = 4.4–8.2) and 2.8 months (95% CI = 2.3–3.3 months) respectively in the mFOLFOX arm, and 5.7 months (95% CI = 4.7–6.7, p = 0.677) and 2.1 months (95% CI = 1.1–3.1 months, p = 0.974) in the mFOLFIRI arm, respectively. ORR of 5.9% and 4.0% (p = 0.663) was achieved in the mFOLFOX and mFOLFIRI groups,,corresponding,and the disease control rate was 66.7% and 64.0% (p = 0.778), respectively.

Molecularly targeted therapy for unresectable biliary tract cancer can be recommended when targetable molecular alterations are identified in the tumor for the treatment of advanced disease refractory to standard chemotherapy, with an ECOG performance status of no worse than 2 and compensated liver function. Molecular alterations of HER2/neu (ERBB2 – overexpression/amplification), BRAFV600E mutations, MSI-H/dMMR microsatellite instability, tumor mutational burden (TMB), and gene translocations of FGFR2, ALK, NTRK, RET are determined using an available validated test [10, 19, 17]. (Table 6)

Table 6 Drug treatment regimens for biliary tract cancer in adults

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

Comment: the use of molecularly targeted therapy is currently optional, but may be recommended in clinical practice upon detection of corresponding molecular-genetic alterations in the tumor after exhaustion of standard therapeutic options, by decision of a medical board.

• HER2/neu (ERBB2) amplification/overexpression in biliary cancer (5%–10% of intrahepatic cholangiocarcinomas and up to 20% in gallbladder cancer) is a potential target for molecularly targeted anti-HER2 therapy: according to the MyPathway basket trial, the combination of #pertuzumab** + #trastuzumab** achieved an objective response rate of 23%, with a median PFS of up to 4 months and a median overall survival of up to 10.9 months [157]. The drug dose is specified in Table 6. In the case of BRAF/RAS co-mutation, a significant decrease in treatment efficacy was noted.

• BRAF mutations are detected in < 5% of cholangiocarcinomas. In the ROAR trial, the combination of #dabrafenib** (a BRAF inhibitor [L01EC: B-Raf serine-threonine kinase (BRAF) inhibitors]) and #trametinib** (a MEK inhibitor [L01EE: Mitogen-activated protein kinase (MEK) inhibitors]) achieved an objective response in 51% of patients with a median PFS of 9 months and OS of 14 months in previously treated patients with the BRAFV600E mutation, suggesting a high probability of clinical benefit in the absence of other options [158]. In the TAPUR trial, the combination of #vemurafenib** (a BRAF inhibitor [L01EC: B-Raf serine-threonine kinase (BRAF) inhibitors]) and #cobimetinib** (a MEK inhibitor [L01EE: Mitogen-activated protein kinase (MEK) inhibitors]) achieved an objective response in 57% of patients with a median PFS of 5.8 months and OS of 15.2 months in previously treated patients with the BRAFV600E mutation, suggesting a high probability of clinical benefit in the absence of other options [176]. Drug doses are specified in Table 6.

• The incidence of deficient mismatch repair (dMMR) in biliary cancer is < 1%. In cases of microsatellite instability-high (MSI-H), potential clinical benefit from immunotherapy can be expected. In the prospective non-randomized phase II KEYNOTE-158 trial, an objective response was observed in 40.9% (of 22 patients) with a median PFS of 4.2 months and a median OS of 24.3 months [159].

• #Selpercatinib, a selective RET kinase inhibitor, was investigated in the phase 1/2 LIBRETTO-001 clinical trial in patients with RET gene translocations. Out of 41 patients, excluding lung and thyroid cancers, the ORR was 43.9% (95% CI = 28.5–60.3%). An objective response was achieved in one patient with cholangiocarcinoma [179]. The drug dose is specified in Table 6.

• FGFR1-4 inhibitors (L01: Antineoplastic agents) (#erdafitinib) are highly effective when oncogenic FGFR1-4 translocations are identified. The efficacy of #erdafitinib was demonstrated in the phase II RAGNAR trial. The ORR was 60%, with a median time to antitumor response of 1.5 months. Median PFS and OS were 8.4 months (95% CI = 5.5–9.7) and 18.7 months (95% CI = 8.9 – not evaluable), respectively. The most common treatment-emergent adverse events were hyperphosphatemia (82.9%), diarrhea (80.0%), and stomatitis (74.3%) [185]. The drug dose is specified in Table 6.

• Appropriate targeted therapy may also be prescribed for other described rare molecular alterations (high TMB, IDH1/2, NTRK, ALK, MET, etc.) or resistance to prior molecularly targeted therapy by decision of the medical board for patients in a satisfactory performance status.

• In disseminated biliary tract cancer (stage IVb, M1) and compromised general condition of the patient (ECOG 2 – see Appendix G), monochemotherapy with gemcitabine** or #capecitabine** is recommended for palliative purposes, taking into account the potential toxicity profile [10, 19, 172]. Drug doses are specified in Table 6.

  Level of evidence – C (level of data reliability 5)

• In case of an unsatisfactory general condition of the patient (ECOG > 2) and severe comorbidities, it is recommended to provide symptomatic therapy; chemotherapy is not recommended [10, 18, 19].

  Level of evidence — C (level of confidence of data — 4).

Comment: the goal of best supportive care is the prevention and relief of disease symptoms and the maintenance of patients' quality of life, regardless of the disease stage and the need for other types of therapy. Palliative chemotherapy in patients with an ECOG performance status of 3–4 (HR = 2.01, p = 0.016), hyperkalemia (HR = 2.19, p = 0.005), and elevated bilirubin levels (HR = 3.17, p < 0.001) is associated with an increased risk of 30-day mortality [18] and is not recommended.

3.4 Radiation Therapy

Radiation therapy is recommended for patients:

• in the adjuvant setting for extrahepatic cholangiocarcinoma [130–132] combined with pyrimidine analogues (L01BC: Pyrimidine analogues). The tumor bed and regional lymph node areas are irradiated at a fractional dose of 2 Gy up to a total dose of 46 Gy, with a sequential boost up to 50–60 Gy to the tumor bed in case of R1/R2 resection [90].

• Stereotactic body radiotherapy for unresectable intrahepatic or hilar tumors when other treatment modalities are unavailable, using a 3–5-day dose fractionation regimen up to a total dose of 30–50 Gy [165].

強B (level of recommendation — B)УДД 3Level of Recommendation — B (Level of Evidence — 3)

Comment: according to meta-analysis data, adjuvant radiotherapy following radical resection in patients with extrahepatic cholangiocarcinoma was associated with improved overall survival (HR = 0.62, 95% CI = 0.48–0.78, p < 0.001) [130]. In patients with extrahepatic cholangiocarcinoma or gallbladder cancer who received adjuvant radiotherapy, 5-year overall survival was higher compared to those who did not receive adjuvant radiotherapy (OR = 0.63, 95% CI 0.50–0.81, p = 0.0002). Adjuvant radiotherapy also improved 5-year overall survival in patients with tumor spread to lymph nodes (OR = 0.15, 95% CI 0.07–0.35, p < 0.00001) and in patients with positive resection margins (OR = 0.40, 95% CI 0.19–0.85, p = 0.02) [131].

Data on radiotherapy volumes and doses are based on a phase II randomized trial in which patients received radiotherapy using either 3D conformal radiation therapy or IMRT technology, although the sequential boost regimen differed: with 3D conformal radiation therapy, after irradiating the lymphatic drainage areas and the tumor bed, a boost was delivered up to 54 Gy and 59.4 Gy in cases of R1 resection, whereas with IMRT technology, the boost was delivered up to 52.5 Gy and 55 Gy in cases of R1 resection [90].

Comment: if the aforementioned techniques are unavailable and/or there is a lack of experience in performing radiotherapy of the biliary tract, the patient should be referred to higher-level expert centers.

LoE BLoCD 4Level of evidence — B (level of confidence of data — 4)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

• Upon completion of treatment for cholangiocarcinoma or after surgical treatment, it is recommended to follow this schedule and monitoring methods:

• for the first 2 years, follow-up examinations are recommended every 3–6 months, and then annually for up to 5 years, in the following scope:

• consultation with an oncologist and physical examination;

• tumor markers CEA, CA 19-9, AFP (if baseline levels were elevated);

• abdominal ultrasound (comprehensive);

• contrast-enhanced CT or MRI of the abdomen;

• computed tomography of the chest;

• cholangiography (if drains are present) [10, 19, 28, 134–136].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

Comments: the goal of follow-up is the early detection of disease progression after treatment completion in order to promptly initiate chemotherapy or surgical resection of metastatic lesions and recurrent tumors.

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 procedures for the provision of medical care approved by the authorized federal executive authority and mandatory for implementation across 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 medical specialists at an ambulatory cancer care center, or, in its absence, at a primary oncology office or the outpatient department of an oncological dispensary (cancer hospital).

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 consultation to an outpatient oncological care center, or, in its absence, to 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, primary oncological office, or outpatient department of an oncological dispensary (oncological hospital) must be performed no later than 3 working days from the date of issuing the referral for consultation. The oncologist of the outpatient oncological care center (in the absence of such a center, the oncologist of the primary oncological office or outpatient department of the oncological dispensary/hospital) arranges for the acquisition of biopsy (surgical) material, as well as the performance of other diagnostic tests necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

If it is impossible to obtain biopsy (surgical) material or perform other diagnostic tests within the medical organization that includes the ambulatory cancer care center (primary oncology office), the patient is referred by the oncologist to an oncological dispensary (cancer 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 timeframe 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, which is 7 working days from the date of prescribing the examinations.

The diagnosis of an oncological disease is established by a medical specialist based on the results of diagnostic examinations, including cytological and/or histological verification of the diagnosis, except for cases where obtaining biopsy and/or puncture material is not feasible.

The oncologist of the ambulatory cancer care center (primary oncology office) refers the patient to an oncological dispensary (cancer hospital) or another medical organization providing medical care to patients with oncological diseases, including those subordinate to a federal executive authority (hereinafter referred to as a federal medical organization), to clarify the diagnosis (in case of the impossibility of establishing a diagnosis, including the extent of the oncological process and the stage of the disease), 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 corresponding International Classification of Diseases for Oncology (ICD-O) 3rd edition codes 8936, 906–909, 8247/3, 8013/3, 8240/3, 8244/3, 8246/3, 8249/3, the oncologist of an oncological dispensary (oncological hospital) or other medical organization providing medical care to patients with oncological diseases shall, in order to determine treatment tactics, 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 for the purposes of this Procedure as national medical research centers).

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 examination results to the pathoanatomical bureau (department) of the fourth group (reference center) through information interaction, including via telemedicine technologies for remote interaction between medical workers;

• digital images obtained from radiation imaging results to the remote diagnostic consultation center for radiation diagnostics through information interaction, including via 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 determined by a medical board (consilium) of physicians, including oncologists, a radiation oncologist, and a neurosurgeon (for nervous system tumors) of a medical organization that includes departments of surgical methods for the treatment of malignant neoplasms, systemic antineoplastic therapy, and radiation therapy (hereinafter referred to as the oncological consilium), including an oncological consilium conducted using telemedicine technologies, with the involvement of other specialist physicians if necessary.

Dispanserization (follow-up) by an oncologist for a patient with a diagnosed oncological disease is established and carried out in accordance with the procedure for follow-up of adults with oncological diseases.

For accounting purposes, information about a newly diagnosed case of an oncological disease is sent within 3 working days by the oncologist of the medical organization where the corresponding diagnosis was established to the oncological dispensary or the organization of a constituent entity of the Russian Federation that performs the registration of patients with newly diagnosed malignant neoplasms, including through the use of the Unified State Health Information System. If the presence of an oncological disease is confirmed in a patient, information about the refined diagnosis is sent from the oncological dispensary or the organization of the constituent entity of the Russian Federation that performs the registration of patients with newly diagnosed malignant neoplasms to the medical organization providing clinical follow-up of the patient.

Specialized, including high-tech, medical care in medical organizations providing medical care to the adult population with oncological diseases is provided on the basis of medical indications stipulated by the regulations on the organization of specialized, including high-tech, medical care.

Specialized medical care, excluding high-tech medical care, in medical organizations subordinate to federal executive authorities is provided based on medical indications provided for in 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, provided for in the appendix to the regulations on organizing the provision of specialized, including high-tech, medical care. (Paragraph 5: to receive specialized medical care on a planned basis, the choice of a federal medical organization is carried out upon the referral of the attending physician.) If the Program involves several federal medical organizations providing specialized medical care for diseases, conditions (group of diseases, conditions) corresponding to the patient's diseases, conditions (group of diseases, conditions), the attending physician is obliged to inform the patient (the patient's legal representative) about the possibility of choosing a federal medical organization, including the potential waiting times for specialized medical care, which may exceed the waiting times established by the program of state guarantees of free medical care to citizens.

The waiting time for the provision of specialized (excluding high-tech) medical care must 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, which is 7 working days.

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 provision on organizing the provision of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, 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 oncological disease treatment (surgery, radiotherapy, drug therapy, etc.) requiring the provision of specialized medical care in an emergency and urgent form

Indications for planned hospitalization in a medical organization are:

1) the need to perform complex interventional diagnostic medical procedures, as well as endoscopic examinations when it is impossible to perform them on an outpatient basis, requiring subsequent monitoring in a round-the-clock 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 by the patient or their legal representative of specialized, including high-tech, medical care in an inpatient or day hospital setting established by the concilium of the medical organization providing cancer care

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

None.

Criteria for Evaluating the Quality of Medical Care

Note: * – if biliary tract tumor pathology is detected on ultrasound, it is recommended to perform computed tomography (CT) of the abdominal organs with intravenous contrast enhancement and/or magnetic resonance imaging (MRI) of the abdominal organs with intravenous contrast enhancement including magnetic resonance cholangiopancreatography.

References

Appendix A1. Working Group Composition

1. Bazin I.S., MD, PhD, Leading Researcher, Department of Antitumor Drug Therapy No. 2, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

2. Breder V.V., MD, PhD, Head of the Department of Drug Treatment, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

3. Virshke E.R., MD, PhD, Head of the X-ray Surgical Department, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

4. Dolgushin B.I., Academician of the Russian Academy of Sciences, Professor, MD, PhD, Director of the Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

5. Kudashkin N.E., PhD, Senior Researcher, Department of Abdominal Oncology No. 2 (Hepato-Pancreato-Biliary Tumors), N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

6. Ledin E.V., PhD, Head of the Chemotherapy Center, Head of the Chemotherapy Department, International Oncology Center at MEDSI Clinical Hospital on Botkinsky Proezd.

7. Lukyanchenko A.B., Professor, MD, PhD, Scientific Consultant, X-ray Diagnostic Department, Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

8. Medvedeva B.M., Professor, MD, PhD, Chief Researcher, X-ray Diagnostic Department, N.N. Blokhin Russian Oncological Scientific Center of the Russian Ministry of Health, Moscow.

9. Moroz E.A., PhD, Senior Researcher, Department of Tumor Pathology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

10. Patutko Yu.I., Professor, MD, PhD, Chief Scientific Consultant, Department of Abdominal Oncology No. 2 (Hepato-Pancreato-Biliary Tumors), N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

11. Pogrebnyakov I.V., Cand. of Med. Sci., Head of the Department of Interventional Radiology, Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

12. Polyakov A.N., Cand. of Med. Sci., Senior Researcher at the Department of Abdominal Oncology No. 2 (Hepato-Pancreato-Biliary Tumors), N.I. Trapeznikov Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

13. Podluzhny D.V., Associate Professor, Cand. of Med. Sci., Head of the Department of Abdominal Oncology No. 2 (Hepato-Pancreato-Biliary Tumors), N.I. Trapeznikov Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

14. Sergeeva O.N., Cand. of Med. Sci., Senior Researcher at the Department of Interventional Radiology, Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

15. Frantsev D.Yu., Cand. of Med. Sci., Physician at the Department of Interventional Radiology, Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

16. Ivanov V.A., Cand. of Med. Sci., Physician at the Department of Radiotherapy, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

17. Fedyanin M.Yu., Professor, Dr. of Med. Sci., Head of the Science Department, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation. Head of the Chemotherapy Service, Moscow Multidisciplinary Clinical Center "Kommunarka", Moscow Healthcare Department. Head of the Department of Oncology, Institute of Postgraduate Professional Education, National Medical Research Center for Surgery named after A.V. Vishnevsky of the Ministry of Health of the Russian Federation

18. Tryakin A.A., Professor, Dr. of Med. Sci., Deputy Director for Research, Head of the Department of Antitumor Drug Therapy No. 2, N.I. Trapeznikov Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

19. Vladimirova L.Yu., Professor, Dr. of Med. Sci., Head of the Department of Drug Treatment of Tumors, Head of the Department of Antitumor Drug Therapy, National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

20. Petkau V.V., Cand. of Med. Sci., Vice-Rector for Research and Innovation, Ural State Medical University, Yekaterinburg.

21. Zukov R.A., Professor, Dr. of Med. Sci., Chief Physician, A.I. Kryzhanovsky Krasnoyarsk Regional Oncology Dispensary. Head of the Department of Oncology and Radiation Therapy with the Postgraduate Training Course, V.F. Voino-Yasenetsky Krasnoyarsk State Medical University.

22. Pokataev I.A., Dr. of Med. Sci., Head of the Chemotherapy Service, Oncology Center No. 1, S.S. Yudin City Clinical Hospital of the Moscow Healthcare Department.

23. Kornietskaya A.L., Cand. of Med. Sci., Leading Researcher at the Department of Drug Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Ministry of Health of the Russian Federation.

24. Varfolomeeva S.R., Professor, Dr. of Med. Sci., Director of the L.A. Durnov Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

25. Kirgizov K.I., Associate Professor, Cand. of Med. Sci., Deputy Director for Research, Acting Head of the Department of Pediatric Bone Marrow Transplantation and Hematopoietic Stem Cells, L.A. Durnov Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation

Medical Care Organization Section

1. Gevorkyan, Tigran G., Deputy Director at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

2. 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

3. 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.

4. 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.

   No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

• oncologists;

• surgeons;

• radiologists;

• interventional radiologists;

• medical oncologists (chemotherapists);

• medical students, residents, and graduate students.

Methods used for evidence collection/selection: electronic database searches; analysis of current scientific developments on the issue of biliary tract cancer in the Russian Federation and abroad; synthesis of practical experience of Russian and foreign specialists.

Table P1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions).

Table P2. Levels of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table P3 – Grades of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Methods used for formulating recommendations – expert consensus.

Economic analysis

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

Method of recommendation validation:

• external expert review;

• internal expert review.

Description of the recommendation validation method

The preliminary version of these guidelines was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations is easy to understand.

Comments were received from primary care oncologists regarding the clarity of the recommendations and their perceived importance as a working tool in daily practice.

The comments received from experts were carefully systematized and discussed by the chairman and members of the working group. Each item was discussed, and the resulting changes made to the recommendations were recorded. If no changes were made, the reasons for refusing to make changes were recorded.

Consultations and expert review

The draft guidelines were also reviewed by independent experts, who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

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

Updates to clinical guidelines: updating is performed at least once every three years, taking into account new information on the diagnosis and management of patients with biliary tract cancer. The proposals generated must take into account the results of a comprehensive evaluation of medicinal products and medical devices, as well as the results of clinical approbation.

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations derived from it.

Appendix A3. Reference Materials

No.

Appendix B. Physician Action Algorithms

Flowchart of diagnosis and treatment of a patient with biliary tract cancer

Appendix C. Patient Information

• Recommendations for surgical treatment complications – contact the operating surgeon.

• Recommendations for chemotherapy complications – contact the medical oncologist (chemotherapist).

If body temperature rises to 38°C or higher:

• contact a medical oncologist.

For stomatitis:

• Diet – mechanical and thermal sparing.

• Frequent mouth rinses (every hour) – chamomile, oak bark, sage, lubricating the oral mucosa with sea buckthorn (peach) oil.

• Treat the oral cavity as prescribed by the medical oncologist.

For diarrhea:

• Diet – exclude fatty, spicy, smoked, sweet, dairy, and high-fiber foods. Lean meat, flour products, fermented milk products, and rice broth are permitted. Drink plenty of fluids.

• Take medications as prescribed by your oncologist.

For nausea:

• Take medications as prescribed by your oncologist.

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

Appendix G1. WHO/ECOG Performance Status Scale

Russian title:WHO Performance Status Scale/ECOG

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

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

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

Type: rating scale

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

Content:

Scoring key (interpretation): provided within the scale itself.