Liver cancer (hepatocellular): clinical guidelines

List of Abbreviations

ALT – alanine aminotransferase

AST – aspartate aminotransferase

AFP – alpha-fetoprotein

HCC – hepatocellular carcinoma

CT – computed tomography

PT – physical therapy

MRI – magnetic resonance imaging

TACE – transarterial chemoembolization

Ultrasound – ultrasound examination

AASLD – American Association for the Study of Liver Diseases

EASL – The European Association for the Study of the Liver

BCLC – Barcelona Clinic Liver Cancer (classification)

ECOG PS – Eastern Cooperative Oncology Group Performance Status

LI-RADS – Liver Imaging Reporting and Data System, a system for reporting and data interpretation of liver imaging.

RECIST – Response Evaluation Criteria in Solid Tumors

mRECIST – modified Response Evaluation Criteria in Solid Tumors

PD1/PD-L1 – programmed cell death 1 / programmed cell death 1 ligand

TNM – (abbreviation for Tumor, Nodus, Metastasis), international classification of malignant tumor stages

** – vital and essential drugs

Terms and Definitions

CTLA4 blocker – a monoclonal antibody blocking cytotoxic T-lymphocyte-associated protein 4.

PD1 blocker – a monoclonal antibody blocking the programmed cell death 1 receptor.

Child-Pugh cirrhosis class – severity of liver function impairment (A, B, C) calculated by the sum of scores.

Computed tomography – a cross-sectional internal diagnostic method.

Magnetic resonance imaging – a cross-sectional internal diagnostic method using the nuclear magnetic resonance effect.

Positron emission tomography – a radionuclide diagnostic method.

Down-staging therapy – aimed at reducing the intrahepatic spread of the tumor process in the absence of extrahepatic lesions.

Transarterial chemoembolization – a method of local treatment for intrahepatic tumors using an embolizing agent combined with a cytotoxic drug.

Transarterial radioembolization – a method of local treatment for intrahepatic tumors using an embolizing agent combined with an isotope.

Ultrasound examination – a non-invasive examination of the body using ultrasound waves.

Bridge therapy – waiting-list therapy aimed at slowing tumor progression and reducing the likelihood of dropout from the transplantation waiting list.

CTLA4 – cytotoxic T-lymphocyte-associated protein 4, also known as CD152. Functions as a receptor with B7.1 or B7.2 molecules as ligands.

Response Evaluation Criteria in Solid Tumours – a set of standardized criteria used to assess changes in tumor size in response to therapy.

Modified Response Evaluation Criteria in Solid Tumors – a set of standardized criteria used to assess changes in tumor size in response to therapy by measuring the vascularized component of the tumor nodule.

Prehabilitation – rehabilitation from the moment of diagnosis until the start of treatment (surgery/chemotherapy/radiation therapy).

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

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

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

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hepatocellular carcinoma (HCC) (hepatocellular cancer, liver cell carcinoma) is the most common (about 85% of cases) malignant liver tumor originating from hepatocytes. Cholangiocarcinoma (cholangiocellular carcinoma), a malignant tumor originating from the epithelium of the intrahepatic bile ducts, is less common, as are mixed hepatocholangiocarcinomas and fibrolamellar carcinoma, which is formally classified as a variant of hepatocellular carcinoma.

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

Hepatocellular carcinoma most frequently develops against the background of liver cirrhosis (about 80% of cases) or chronic inflammation of any etiology: viral hepatitis B and C, alcoholic and non-alcoholic steatohepatitis, primary sclerosing and autoimmune hepatitis, due to exogenous toxic liver damage (under the action of aflatoxins, vinyl chloride, steroid hormones), as well as in hereditary diseases (alpha-1 antitrypsin deficiency, tyrosinemia, and hemochromatosis) and immune system disorders that cause liver damage resulting in chronic hepatitis and cirrhosis. Viral hepatitis B and C are the most common risk factors, causing HCC in 50% and 15% of cases, respectively. With the introduction of hepatitis B vaccination and effective antiviral therapy for hepatitis C, the role of viral hepatitis is gradually declining. In developed countries, the role of non-alcoholic fatty liver disease is increasing [1–3]. Less than 10% of HCC cases develop in healthy liver tissue.

1.3 Epidemiology of the Disease or Condition

In the Russian Federation, HCC is relatively rare. In 2019, 9,324 new cases of HCC and intrahepatic bile duct cancer were registered in Russia, and 10,430 patients died from this cause [4]. According to statistical reports for the period from 2009 to 2019, the Russian Federation shows the highest increase among oncological diseases — more than 48% — in the crude incidence rate (for men +57%) with more than a 29% increase in the standardized incidence rate of HCC. Mortality dynamics for HCC indicate a 21.6% increase in the absolute number of liver cancer deaths and a 5.65% increase in the standardized mortality rate (per 100,000 population). Notably, mortality exceeds the incidence of primary liver cancer by ~1,100 cases in 2019.

1.4 Features of Coding the Disease or Condition

C22.0 Liver cell carcinoma. Hepatocellular carcinoma.

D37.6 Neoplasm of uncertain or unknown behavior of liver, gallbladder and bile ducts.

1.5 Classification of the disease or condition

1.5.1 International histological classification (2019)

Benign hepatocellular tumors:

Hepatocellular adenoma 8170/0

Malignant and precancerous neoplasms:

Malignant hepatocellular tumors:

Hepatocellular carcinoma 8170/3

Hepatocellular carcinoma (fibrolamellar subtype) 8171/3

Hepatocellular carcinoma, scirrhous subtype 8172/3 Hepatocellular variant, clear cell type 8174/3

Hepatocellular variant, steatohepatitic subtype 8174/3

Hepatocellular variant, macrotrabecular massive subtype 8174/3

Hepatocellular carcinoma, chromophobe subtype 8174/3

Hepatocellular carcinoma, with neutrophil infiltration 8174/3

Hepatocellular carcinoma, with lymphocyte infiltration 8174/3

Hepatoblastoma 8970/3

1.5.2. Staging

TNM staging (8th edition, 2017) [5].

T – primary tumor.

T_X – primary tumor cannot be assessed.

T0 – no evidence of primary tumor

T1 – solitary tumor.

T1a – solitary tumor ≤2 cm in greatest dimension with or without vascular invasion.

T1b – solitary tumor >2 cm in greatest dimension without vascular invasion.

T2 – solitary tumor >2 cm with vascular invasion, or multiple tumors ≤5 cm in greatest dimension.

T3 – multiple tumors, including at least one tumor >5 cm in greatest dimension.

T4 – solitary tumor or multiple tumors of any size with invasion of a major branch of the portal vein or hepatic vein, or invasion of adjacent organs, including the diaphragm (except the gallbladder), or with invasion of the visceral peritoneum.

N – regional lymph node involvement. Regional lymph nodes are the lymph nodes of the hepatic hilum (located in the hepatoduodenal ligament).

N_X – regional lymph nodes cannot be assessed.

N0 – no regional lymph node metastasis.

N1 – regional lymph node metastases are present.

M – distant metastasis.

M_X – distant metastasis cannot be assessed.

M0 – no distant metastasis.

M1 – distant metastasis present.

pTNM – pathological classification.

Requirements for determining pT, pN, and pM categories correspond to those for T, N, and M categories (Table 1).

G – histopathological differentiation.

G_x – grade of differentiation cannot be assessed.

G₁ – well differentiated.

G₂ – moderately differentiated.

G₃ – poorly differentiated.

G₄ – undifferentiated.

Table 1. Stage grouping for hepatocellular carcinomas (UICC)

Barcelona staging system

The Barcelona Clinic Liver Cancer (BCLC) classification is the most commonly used staging system for HCC, which takes into account tumor extent, liver function, physical status of the patient, and expected treatment efficacy (see Figure A1 in Appendix A3) [6].

There are 5 stages: from 0 – very early and A – early to D – terminal. BCLC stages, as well as disease prognosis and treatment tactics, may change upon disease progression or effective treatment. It should be noted that the classification has prognostic significance for patients with HCC regardless of the presence of liver cirrhosis. An important feature of this classification is that it proposes a treatment algorithm depending on the disease stage [7].                             

• Very early stage (BCLC 0) – solitary tumor less than 2 cm in diameter with preserved liver function.

• Early stage (BCLC A) – solitary liver tumor of any size or up to 3 nodules with a maximum size of up to 3 cm, without invasion of major hepatic vessels or adjacent anatomical structures, in a patient without tumor-specific symptoms, in a satisfactory general condition (ECOG 0) and with preserved liver function.

• Intermediate stage (BCLC B) – cases of isolated asymptomatic multinodular liver involvement without macrovascular invasion, in patients in satisfactory condition (ECOG 0) and with preserved liver function. This stage is divided into three substages: B1 with limited intrahepatic involvement, having prospects for radical treatment if downstaged to BCLC A as a result of effective chemoembolization/systemic therapy; B2 – limited multifocal involvement; and B3 – a substage with diffuse and/or multi-focal bilobar involvement, more suitable for systemic therapy.

• Advanced stage (BCLC C) – general condition (ECOG 0–2), tumor of any size with or without invasion of major hepatic vessels and/or extrahepatic spread, and with preserved liver function.

• Terminal stage (BCLC D) – cases with poor general condition (tumor/cirrhosis) and decompensated liver function (CTP B/C ≥ 8 points).

1.6 Clinical presentation of the disease or condition

The clinical presentation is generally insidious and lacks specific symptoms. HCC is most often diagnosed at later stages. The spectrum of manifestations may be determined by the underlying liver disease, cirrhosis, and complications of the tumor process.

In the early stages of the disease, symptoms are mild. Therefore, patients do not attach much importance to them and do not seek medical care. Over time, symptoms increase and become more pronounced: the onset of pain is most often associated with the invasion of anatomical structures, including major vessels, with the formation of tumor thrombi, as well as with metastatic organ involvement. The main complaints in advanced disease include severe general weakness, lethargy, fatigue, abdominal enlargement, discomfort and pain in the right upper quadrant, as well as fever and lower extremity edema. Paraneoplastic syndromes occur in a small proportion of patients and manifest as hypoglycemia, erythrocytosis, and hypercalcemia.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for diagnosis/condition establishment – based on pathognomonic clinical and radiological findings, results of morphological examination of biopsy or surgical material, laboratory tests aimed at assessing liver function, and instrumental evaluation of the extent of the tumor process and severity of concomitant diseases.

HCC most commonly develops against the background of chronic liver disease – liver cirrhosis, viral hepatitis, steatohepatitis – which, like the tumor process, can manifest with specific symptoms, require specific therapy, competitively affect quality of life, and worsen survival. As part of a multidisciplinary patient assessment, it is necessary to evaluate liver functional reserves, the severity of underlying liver pathology, and the extent of the tumor process.

2.1 Complaints and Anamnesis

2.2 Physical Examination

Comments: Efforts should be made to differentiate tumor-induced symptoms from longstanding symptoms of liver cirrhosis and its complications.

2.3 Laboratory Diagnostics

Comments: An AFP test result is considered positive if the AFP level is >100 ng/mL [12] or if it increases by 7 ng/mL per month based on 3 consecutive measurements [13]. It should be borne in mind that AFP levels may also elevate in chronic liver diseases, such as acute and chronic viral hepatitis, in other malignancies (e.g., hepatoid adenocarcinoma of the stomach, germ cell tumors), and during pregnancy.

Assessment of liver functional status

Comments: Liver cirrhosis, a frequent comorbidity, determines the tolerability of core treatment modalities—sometimes precluding treatment entirely—and negatively impacts overall survival in competition with HCC. The course of cirrhosis is driven by the activity of its etiological factor(s) and complications; clinical and laboratory monitoring of liver function by the oncologist throughout the follow-up period is critical. In collaboration with a gastroenterologist or general practitioner, complications of liver cirrhosis must be prevented, identified, and treated in a timely manner.

2.4 Instrumental Diagnostics

• In cases of suspected or identified small focal liver lesions in a patient at high risk for hepatocellular carcinoma (liver cirrhosis of any etiology Child-Pugh class A and B, Child-Pugh class C liver cirrhosis while on the liver transplant waiting list, patients with chronic hepatitis B at intermediate or high risk of HCC development based on the PAGE-B score of 10–17 and ≥18 points, respectively, and patients with stage F3 liver fibrosis depending on other individual risk factors) regardless of the AFP level, or upon a positive AFP test result in patients with suspected HCC, it is recommended to perform multiphase contrast-enhanced computed tomography (CT) of the liver and abdominal cavity and/or contrast-enhanced magnetic resonance imaging (MRI) of the liver and abdominal cavity, regardless of ultrasound (US) findings, to clarify the diagnosis and extent of tumor spread [8, 9, 14, 16–18].

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

Comment: Diagnosis of early HCC and timely initiated treatment are crucial for improving patient prognosis and quality of life, thereby increasing long-term survival. The uptake and washout characteristics of extracellular MRI contrast agents in arterial, venous, and delayed phases often fail to reliably detect and differentiate neoplasms, especially small ones. Therefore, preference should be given to hepatotropic contrast agents. The hyperintensity of the liver parenchyma in the hepatospecific phase allows clear visualization of small hypointense foci and, considering their enhancement patterns in prior phases, differentiates early HCC from other hepatic neoplasms, including regenerative and dysplastic nodules, which in some cases may alter the tumor staging.

Comment: A number of systematic reviews and meta-analyses of randomized clinical trials have proven the high diagnostic performance of MRI using the hepatospecific contrast agent gadoxetic acid combined with diffusion-weighted imaging (DWI) compared to CT and MRI with extracellular contrast agents in the detection and differential diagnosis of HCC.

Comment: Ultrasound is used at the screening stage in high-risk groups for HCC, during percutaneous biopsy and interventional procedures, and occasionally for monitoring treatment efficacy. Assessment of portal vein patency is mandatory. The sensitivity of ultrasound is low for detecting small nodules. Contrast-enhanced ultrasound has an advantage in identifying hypervascular nodules, which can be useful in the differential diagnosis of focal liver lesions.

Comment: the diagnosis of hepatocellular carcinoma can be considered well-founded without morphological verification if, in a cirrhotic liver, imaging by one of the methods (multiphase CT or MRI) reveals features typical for HCC, namely: diffuse (non-ring) contrast enhancement of a tumor >1 cm in size in the late arterial phase and contrast washout in the venous phase; in tumor nodules >2 cm in size, detection of a pseudocapsule in the delayed (equilibrium) phase; tumor growth by less than 6 months by 50% or an increase in tumor size by at least 5 mm over 6 months (American Association for the Study of Liver Disease, AASLD/Liver Imaging Reporting and Data System, LI-RADS; The European Association for the Study of the Liver, EASL 2018; Asian Pacific Association for the Study of the Liver, APASL/National Comprehensive Cancer Network, NCCN). The LI-RADS radiological classification can be used in the differential diagnosis of liver neoplasms [9,24]. Randomized trials have proven that the LI-RADS category 4-5 has high specificity (95-100%) for high-risk HCC patients with a nodule >10 mm in size [25,26].

Comment: the use of gadoxetic acid-enhanced MRI demonstrates the highest values of sensitivity, specificity, and accuracy in the detection and differential diagnosis of HCC compared to contrast-enhanced CT and contrast-enhanced MRI using extracellular contrast agents, thereby allowing the selection of optimal patient management tactics as well as contributing to a reduction in the recurrence rate and mortality.

• For morphological confirmation of the diagnosis, it is recommended that patients with suspected HCC undergo ultrasound/CT-guided liver biopsy to clarify the diagnosis [8,9] in the following cases:

  – if CT or MRI suspects a pathological lesion in a non-cirrhotic liver;

  – if it is necessary to rule out a malignant liver tumor in the absence of specific radiographic signs of HCC in a cirrhotic liver

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

Comments: core needle biopsy of a liver tumor obtaining a tissue core (core biopsy) is preferable to fine-needle aspiration biopsy. Biopsy is recommended for small tumor size (<2 cm) and typical HCC blood supply, atypical vascularization of a node >2 cm in size, discrepancies in the description and interpretation of dynamic contrast-enhanced studies combined with a normal or slightly elevated AFP level, and the detection of any tumor formation outside a cirrhotic liver [29]. A negative biopsy result does not rule out the diagnosis of a malignant liver tumor and implies further follow-up with the possibility of repeat biopsies. Biopsy of a focal lesion in a cirrhotic liver is not necessary if: 1) no treatment is planned due to decompensated cirrhosis and/or other severe pathology; 2) liver resection is planned; 3) in cirrhosis, multiphasic contrast-enhanced CT and MRI describe signs specific to HCC (uneven enhancement of the node in the arterial phase, followed by washout in the venous phase) [30, 31].

For the confirmatory diagnosis of early and well-differentiated HCC, the International Consensus Group for Hepatocellular Neoplasia recommends a panel of 3 immunohistochemical markers – HSP70 (HSPA7), glypican 3 (GPC3), and glutamine synthetase (GS), and for the detection of prognostically unfavorable cases – cytokeratin 19 (CK 19). In diagnostically complex cases, it is advisable to send histological specimens for examination to specialized centers. If mixed hepatocholangiocarcinoma is detected, it is advisable to determine the microsatellite status of the tumor.

2.5 Other Procedures

Diagnostic angiographic techniques are an essential component of endovascular therapeutic intervention in patients with HCC, allowing for the assessment of the celiac trunk and its branches, clarification of the anatomical variant of hepatic blood supply, determination of the degree of vascularization of tumor nodes, and identification of arterio-portal or arteriovenous shunts. The obtained diagnostic data are of great importance in determining both the feasibility of performing and the planning of subsequent transarterial chemoembolization (TACE) of the liver.

When pronounced arteriovenous shunting or an arterioportal shunt with contrast enhancement of the main portal vein trunk or its lobar branches is detected in patients with HCC, TACE is not indicated. Patients with arteriovenous shunting are indicated for hepatic artery embolization at the first stage of endovascular treatment (prior to TACE) in order to occlude the arteriovenous fistulas [36,37].

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

The development of a treatment plan based on diagnostic results should be the responsibility of a specialized multidisciplinary HCC team operating within specialized centers. When choosing a treatment strategy for patients with HCC, priority should be given to specialized antitumor treatment using methods that increase survival.

Radical treatment for early localized HCC includes liver resection, orthotopic liver transplantation, and local ablative destructive methods (radiofrequency ablation, microwave ablation, etc.) [8,9,14,131,132].

Palliative treatment of HCC aims to achieve control over disease manifestations and is designed to increase the life expectancy and improve the quality of life of patients. Specialized palliative treatment includes interventional radiological treatment (various types of embolization), radiotherapy, and systemic chemotherapy [8,9,14,156,157].

The treatment plan is developed based on the results of an objective examination by a multidisciplinary team of specialists (including a radiologist, surgeon (hepatologist), endovascular diagnostic and treatment specialist, oncologist, radiation oncologist, diagnostic radiologist, pathologist, and gastroenterologist) experienced in working with HCC patients at specialized centers.

Since HCC is diagnosed in a cirrhotic liver in the majority of cases, the prognosis for these patients is determined not only by the extent of tumor spread, but also by the severity of liver dysfunction and the patient's performance status. A major negative impact on the prognosis of underlying cirrhosis is exerted by the persistent cause of its development – viral hepatitis, alcohol abuse.

3.1 Surgical Treatment

Comments: the main condition to be met when planning liver resection is the preservation of an adequate blood supply, as well as venous and biliary drainage in the anticipated remaining liver parenchyma. The volume of the anticipated remaining liver parenchyma should be at least 25% (of the unaffected parenchyma) in the absence of laboratory and instrumental signs of cirrhosis, and at least 40% in their presence. If the parenchymal volume is insufficient, interventional radiological embolization of the portal vein branch in the anticipated resected lobe of the liver is possible.

If the patient has laboratory and instrumental signs of cirrhosis, the degree of hepatocellular dysfunction (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) should be taken into account.

In specialized centers (with trained personnel and equipment), liver resections can be performed using a minimally invasive video-endoscopic approach. Subcapsular formations, as well as nodules located in the lateral sectors of the liver, are preferred when planning this approach.

It should be noted that a large tumor size and/or multiple intrahepatic lesions, invasion of major vessels, and metastatic involvement of regional lymph nodes are not absolute contraindications to liver resection, although the results of surgical treatment in these cases are predictably poorer.

Comments: the so-called Milan criteria are most commonly used: size of a single tumor ≤5 cm or no more than 3 nodules in the liver with a maximum diameter of ≤3 cm and no vascular invasion [6,8,9]. Indications and contraindications for liver transplantation are determined by a transplant surgeon. Liver transplantation in patients with unresectable HCC (e.g., fibrolamellar carcinoma) in the absence of underlying liver disease (cirrhosis, hepatitis) is the most radical method. The Milan criteria should not be applied to such patients. Important: strictly no extrahepatic spread, preferably no macrovascular invasion [46–49].

To ensure objective staging and patient selection for liver transplantation, extrahepatic spread must be ruled out. Chest CT is a mandatory imaging study for patients with HCC being evaluated for liver transplantation [46].

• Bridge therapy (bridging therapy aimed at slowing tumor progression and reducing the likelihood of drop-out from the transplantation waiting list) is recommended for patients awaiting liver transplantation to increase the likelihood of successful transplantation, improve selection, and rule out aggressive cases of HCC [6,9,50,51].

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

• Down-staging therapy (aimed at reducing the intrahepatic extent of the tumor process in the absence of extrahepatic changes) is recommended for patients with localized HCC exceeding standard criteria for liver transplantation, provided that an objective antitumor response to locoregional and/or systemic therapy is achieved, reducing the intrahepatic extent to the accepted liver transplantation criteria [45].

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

Comments: Bridge therapy and down-staging include ablation, transarterial chemoembolization, liver resection, drug therapy, or a combination of methods. Liver transplantation following the reduction of the intrahepatic tumor extent to accepted transplantation criteria as a result of antitumor therapy is associated with a significant increase in overall survival compared to conservative treatment methods.

3.2 Local tumor destruction methods

Comments: The main criterion in determining indications is the technical feasibility of the intervention with a minimal risk of complications. No more than 5 nodules with a diameter of ≤3 cm are eligible for destruction. Destruction of larger nodules is possible, but the local recurrence rate increases significantly for tumors >3 cm in maximum dimension. In some cases, it is advisable to perform ablation after prior transarterial (chemo-)embolization of the liver tumor or to perform energy ablation combined with percutaneous intratumoral ethanol injection (chemical ablation). Local destruction is contraindicated in multiple liver lesions, decompensated cirrhosis (Child-Pugh class C), extrahepatic disease manifestations, the presence of a portosystemic shunt, fixed adherence of the tumor nodule to adjacent hollow organs, or to extra-(intra-)hepatic tubular structures [64–66]. Radiofrequency ablation, microwave ablation, and cryoablation are recommended as methods of local percutaneous and laparoscopically assisted energy ablation. Percutaneous ethanol injection is recommended as a method of local chemical ablation [67–70].

3.3 Transarterial chemoembolization

Comments: The Barcelona Clinic Liver Cancer (BCLC) staging system (2022 version) implies a sequential change in treatment tactics; however, among the expert community, the combination of locoregional treatment and systemic therapy is being discussed for patients with intermediate and advanced stages in order to increase the objective response rate, progression-free survival (PFS), and overall survival (OS).

Comments: relative contraindications to TACE include a transjugular intrahepatic portosystemic shunt (TIPS); segmental or subsegmental non-tumor portal vein thrombosis; and patients with a tumor burden >50% of the liver volume. [6,80,81,83,133,134].

Comments: Diagnostic FPCT has demonstrated superiority in detecting tumors and tumor vessels compared with digital subtraction angiography (DSA) and allows for the detection of previously invisible intrahepatic lesions. In addition, unenhanced FPCT is used to assess the distribution of the embolization agent during the procedure and to visualize the exact anatomical region of the liver treated via the transarterial route immediately after the intervention. This can be useful for identifying incomplete embolization of the tumor focus due to extrahepatic "parasitic" vessels in subcapsular locations or additional feeding vessels from the contralateral liver lobe when the tumor is located on the interlobar boundary, thus guiding the patient for subsequent sessions of transarterial chemoembolization, as well as for the early detection of non-target embolization if the embolizing agent enters healthy organs and tissues.

The choice of TACE technique in patients with HCC depends on the BCLC stage, clinical situation, technical conditions, and treatment plan. Any transcatheter intervention requires the use of a microcatheter, regardless of the level of embolizing material delivery (superselective—at the level of segmental, subsegmental, or tumor-feeding arteries), to minimize the risk of vascular injury and maintain free antegrade blood flow [141-146].

The use of a superselective technique in TACE helps increase the rate of complete objective responses, prolong overall survival, and reduce the incidence of adverse events [142–146]. The most commonly used antineoplastic agents are doxorubicin** or epirubicin** at a single dose determined by the manufacturer of the carrier and its volume. The maximum safe single dose of doxorubicin that can be administered to an adult patient is 150 mg. [147]

The endpoint of superselective conventional oil-based TACE is the angiographic appearance of a "dead tree" or "winter tree" with occlusion of small vessels feeding the tumor, while preserving blood flow in the major lobar and segmental arteries for subsequent embolization. In superselective TACE with drug-eluting beads, the microspheres are injected under continuous fluoroscopic guidance until blood flow stasis is achieved, targeting 10 heartbeats [148,149].

Comments: comparable modalities should be used to assess the effect of TACE (all subsequent scans must match the initial one). If there is no enhancement (total necrosis (CR)) in the treatment area, repeat TACE is not indicated. If tumor vascularity persists in the treatment area (partial response or stable disease (PR or SD)), repeat TACE is performed with response evaluation by contrast-enhanced CT and/or MRI in 4–6 weeks. In case of complete response (CR), subsequent follow-up should be performed every 3 months [6,151].

3.4 Transarterial radioembolization

• Endovascular vascular embolization for neoplasms of the liver and biliary tract using yttrium-90 (Y⁹⁰) – transarterial radioembolization – is recommended as one of the options for HCC patients at BCLC stage A as bridge therapy, and at BCLC stage C with main vein thrombosis who are not eligible for systemic therapy, to improve treatment outcomes and patient survival [6,8,9,50,85].

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

Comments: main contraindications to transarterial radioembolization include involvement of >70% of the liver volume and presence of an arteriovenous shunt.

3.5 Radiation therapy

Comment: radiation therapy is performed as 3D conformal radiotherapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or image-guided stereotactic body radiation therapy (SBRT). The use of stereotactic body radiation therapy appears to be optimal. It is recommended to use a 3- or 5-day dose fractionation regimen up to a total dose of 30–50 Gy in patients with preserved liver function (Child-Pugh class A or B ). SBRT can be considered as an alternative to ablation/embolization methods when these treatments have failed or are contraindicated. If stereotactic body radiation therapy is not feasible, radiation therapy can be administered with a fraction dose of 1.8 Gy up to a total dose of 45 Gy, followed by a sequential local boost to the tumor up to a total dose of 50–60 Gy.

3.6 Medical treatment

Significant expansion of the arsenal of effective drug treatment options for advanced HCC in recent years, especially in the second- and third-line settings, in the absence of reliable comparative efficacy data, requires a balanced approach based on consideration of numerous individual patient and disease parameters. No predictive factors of efficacy for immunotherapy, protein kinase inhibitors, and cytotoxic chemotherapy are known for HCC.

• Systemic therapy is recommended by an oncologist for HCC patients to improve survival and control tumor growth in the following cases [87–93]:

  - presence of objective signs of the tumor process and a satisfactory general condition (0–1 points on the ECOG scale (Appendix G2));

  – preserved liver function (Child-Pugh class A or B, 5–8 points);

  - inability to use local treatment methods (resection, liver transplantation, (chemo)embolization of tumor nodes);

  - intrahepatic localized HCC (as waiting-list therapy for transplantation, in combination with TACE, or after chemoembolization);

  - extrahepatic metastasis and/or disease progression in the liver after local treatment methods.

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

The general algorithm for drug treatment is presented in Appendix A3.

Comments: drug therapy requires morphological (cytological or histological, which is preferable) verification of the tumor process, since 1% to 10% of primary liver tumors present cases where the tumor contains a combination of hepatocellular carcinoma and cholangiocarcinoma. Verification is not required if, against the background of an established diagnosis of liver cirrhosis, multiphasic CT or dynamic contrast-enhanced MRI by an experienced radiologist reveals an HCC-typical radiological picture of a hypervascular liver tumor (with contrast "washout" in the venous phase).

Decompensation of liver cirrhosis competitively affects overall survival, but is not a contraindication to anti-tumor therapy. Regular clinical and laboratory monitoring of liver function, active prevention of complications of liver cirrhosis, and their treatment under the supervision of a gastroenterologist are necessary. In patients with HCC against the background of newly diagnosed decompensated liver cirrhosis, a gastroenterologist consultation should be performed to select and conduct therapy for cirrhosis complications; upon improvement of liver function and a satisfactory patient condition, a re-discussion of anti-tumor treatment prospects at a multidisciplinary team meeting is justified. In patients with recent (up to 3 months ago) bleeding, arterial or venous thrombosis, clinically pronounced and poorly compensated cardiovascular pathology, treatment with protein kinase inhibitors or direct neoangiogenesis inhibitors is associated with a high risk of complications.

In decompensated cirrhosis (more than 8 points on Child-Pugh), cytotoxic treatment is not recommended, as it is associated with a high risk of chemotherapy complications and worsening liver failure.

The probability of viral hepatitis reactivation during systemic anti-tumor therapy is low, although in cases of HBsAg-positive chronic hepatitis B, simultaneous antiviral therapy with nucleoside analogues is required throughout the entire anti-tumor treatment.

3.7 Supportive therapy and treatment of underlying liver disease

Comments: treatment is carried out under the supervision of an oncologist continuously until the appearance of objective (confirmed by CT/MRI) signs of disease progression, unmanageable toxicity, or decompensation of concomitant diseases. According to a phase 3 randomized clinical trial (ImBrave150), the combination of atezolizumab** and bevacizumab** demonstrated a significant advantage over sorafenib** in overall survival (median OS – 19.2 months vs. 13.4 months) and progression-free survival (median 6.9 months vs. 4.3 months). Relative contraindications to therapy include autoimmune diseases, active hepatitis B and C co-infection, upper gastrointestinal bleeding within the previous 6 months, or a high risk of bleeding from esophageal and gastric varices (grade 3 esophageal varices on effective prophylaxis with non-selective β-blockers, < 2 weeks after band ligation of grade 3 esophageal varices).

• The preferred first-line treatment choice may also be the combination of the anti-CTLA4 agent tremelimumab** at a dose of 300 mg as a single initial dose with the PD-L1 inhibitor durvalumab** at a dose of 1500 mg on day 1 of the first cycle, followed by durvalumab monotherapy (STRIDE regimen) once every 4 weeks [129].

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

Comments: treatment is carried out under the supervision of an oncologist continuously until the appearance of objective (confirmed by CT/MRI) signs of disease progression, unmanageable toxicity, or decompensation of concomitant diseases. According to a phase 3 randomized clinical trial (Himalaya), the combination of durvalumab** and tremelimumab** demonstrated an advantage over sorafenib** in overall survival (median OS – 16.4 months vs. 13.8 months). In addition, durvalumab** monotherapy demonstrated non-inferior overall survival compared with sorafenib (median OS – 16.6 months vs. 13.8 months). It should be noted that the pivotal Himalaya study did not include patients with advanced thrombosis (type 4–5 – main portal vein trunk).

• As alternative options for 1st-line systemic therapy of HCC, protein kinase inhibitors sorafenib** or lenvatinib** are recommended [87–90].

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

Comments: treatment is carried out under the supervision of an oncologist continuously until the appearance of objective (confirmed by CT/MRI) signs of disease progression, unmanageable toxicity, or decompensation of concomitant diseases. Treatment of HCC progressing after liver transplantation (against the background of immunosuppressive therapy) is accompanied by more pronounced toxicity. The tolerability of lenvatinib** in this group of patients has not been sufficiently studied; it is recommended to start with 8 mg/day, and if well tolerated for 10–14 days, the dose can be increased to 12 mg/day.

The dosing regimen of lenvatinib** depends on the patient's baseline weight: for patients with a body weight of ≥60 kg, treatment starts with a once-daily dose of 12 mg, and for patients with a weight of <60 kg – with a once-daily dose of 8 mg.

Toxic effects associated with the use of sorafenib** and lenvatinib** (diarrhea, arterial hypertension, hand-foot syndrome) are biological predictors of better survival provided therapy is continued; it is advisable to take all measures to correct toxic effects, primarily timely reduction of the daily dose of the drug.

• In patients with initial signs of liver cirrhosis decompensation or in case of contraindications to the use of protein kinase inhibitors as an alternative (Child-Pugh B, 7–8 points), immunotherapy with nivolumab** is recommended to improve tumor growth control and patient survival in one of the recommended treatment regimens [94].

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

3.6.1 First-line systemic therapy for HCC

All known randomized placebo-controlled trials of 2nd-line treatment for advanced HCC were performed in a population of patients who received sorafenib** as 1st-line therapy. To date, there are no data on the efficacy of other options after immunotherapy or lenvatinib**. Therefore, the choice of 2nd-line therapy is determined by the previously used treatment option:

A) after immunotherapy, protein kinase inhibitors sorafenib** or lenvatinib**, regorafenib**, cabozantinib**, or ramucirumab** (at an AFP level >400 ng/ml) are considered; the efficacy of combination immunotherapy is unknown.

B) after protein kinase inhibitors, regorafenib**, cabozantinib**, ramucirumab**, or immunotherapy can be used.

C) after protein kinase inhibitors, the combination of atezolizumab** + bevacizumab** or one of the 1st-line immunotherapy options can be used.

Comments: regorafenib** is prescribed if tolerability to sorafenib** at a dose of ≥400 mg/day was demonstrated in the 1st line of therapy, provided the patient has a satisfactory performance status (ECOG 0/1) and compensated liver function (Child-Pugh class A) at the standard regimen of 160 mg once daily on days 1–21, 4-week cycle; for patients with risk factors for toxicity (episodes of liver cirrhosis decompensation during sorafenib** at 400 mg/day, poorly controlled comorbidities), it is prescribed at a starting dose of 120 mg once daily on days 1–21 of a 4-week cycle. When initiating treatment at a reduced dose, in the absence of grade II or higher toxicity, increasing the daily dose to the standard recommended dose (160 mg/day) 10–12 days after the start of the cycle is justified.

Comments: indicated for HCC progression on sorafenib** therapy in patients with an AFP level $\ge$400 ng/mL. The drug is prescribed to patients who tolerated sorafenib** therapy satisfactorily ($\ge$400 mg/day).

For pembrolizumab: Strength of recommendation – B (Level of evidence – 2)

For nivolumab: Strength of recommendation – C (Level of evidence – 4)

Comments: patients are prescribed nivolumab** in one of the dosing regimens (regimen selection does not affect clinical efficacy) or pembrolizumab** until clinically significant tumor progression. The use of nivolumab** is justified in patients with Child-Pugh class B cirrhosis (7–8 points). There is no evidence of a negative impact of immunotherapy on the course of liver cirrhosis.

Fibrolamellar carcinoma is generally resistant to therapy with anti-PD-1 monoclonal antibodies (immune checkpoint inhibitors). When tyrosine kinase inhibitors (sorafenib**) are used in the 1st and 2nd lines, progression-free survival is significantly higher than in patients receiving gemcitabine** with platinum-based drugs (cisplatin** or oxaliplatin**) as chemotherapy [130].

Comments: combination immunotherapy regimen: nivolumab** 1 mg/kg + ipilimumab** 3 mg/kg IV once every 3 weeks for 4 cycles, followed by maintenance therapy with nivolumab** at 240 mg once every 2 weeks or 480 mg once every 4 weeks until disease progression or unacceptable toxicity; a phase 1–2b study reported an objective response rate of 32%, with a median overall survival in the group of 22.8 months.

Comments: platinum-containing regimens combined with #gemcitabine** [99, 121, 124] are used (Table 2). For mixed histological variants—hepatocellular cholangiocarcinoma—cytotoxic chemotherapy is preferred in 1st-line treatment, as life expectancy is considered to be determined by the cholangiocellular component of the tumor as the most malignant one. It does not increase life expectancy and is effective in less than 20% of cases.

Comments: serial monitoring of plasma AFP levels is indicated in patients with initially high baseline values; several studies have noted a direct correlation between treatment efficacy and changes in AFP concentration.

3.6.2 Second- and third-line systemic therapy for HCC

• In patients with HCC, antiviral therapy for concomitant chronic hepatitis B (HBV DNA >2$\times$10² IU/mL) with nucleotide/nucleoside analogs (entecavir** or tenofovir**) and chronic hepatitis C with direct-acting antivirals (glecaprevir/pibrentasvir** or sofosbuvir/velpatasvir**) is recommended simultaneously with medical or interventional radiological treatment, regardless of the severity of cytolytic syndrome, to improve patient survival. Antiviral therapy after surgical treatment (resection, liver transplantation) may improve long-term outcomes [14,52–56,148].

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

Comments: concurrent systemic chemotherapy and direct-acting antiviral therapy are feasible in patients with compensated liver function. No clinically significant drug-drug interactions between direct-acting antivirals and HCC chemotherapy agents have been described.

Comments: if medical treatment for grade III esophageal and/or gastric varices is ineffective, in the presence of bleeding risk, or for secondary prophylaxis of recurrent hemorrhage, variceal band ligation or sclerotherapy is performed [6,9,102,103,151].

Comments: the highest probability of esophageal/gastric variceal bleeding in patients with liver cirrhosis occurs in the presence of tumor thrombosis of the main portal vein and its major branches. Information on the management of liver cirrhosis is provided in the clinical guidelines "Liver Cirrhosis and Fibrosis".

3.8. Analgesic therapy

• To manage chronic pain in patients with HCC, it is recommended to use nonsteroidal anti-inflammatory and antirheumatic drugs, antidepressants, antiepileptic drugs, papaverine and its derivatives, local anesthetics, pyrazolone derivatives, opioid analgesics, mixed-mechanism opioid analgesics, anxiolytics, systemic antihistamines, and centrally acting muscle relaxants [122,123].

GCR ALEL 2Grade of Recommendation – A (Level of Evidence – 2)

Comments: the choice of pain management method is determined by the severity of the patient's pain. A detailed algorithm for pain management is presented in the methodological recommendations [5].

When selecting pharmacotherapy for pain, the specific metabolism of drugs in the setting of liver cirrhosis and/or liver failure should be taken into account: nonsteroidal anti-inflammatory drugs negatively affect liver function when used chronically.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• Following surgical interventions, it is recommended that patients with HCC undergo rehabilitation based on general principles of rehabilitation after surgery, TACE, and/or chemotherapy to improve clinical and functional outcomes [106].

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

4.1 Pre-rehabilitation

• To improve cardiorespiratory endurance during the preparation stage for anti-tumor treatment, patients with HCC are recommended to perform home-based exercise therapy (moderate-intensity aerobic and anaerobic physical activity) for at least 15 minutes a day, 6–7 days a week, to reduce the rate of postoperative complications [106].

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

• Nutritional support is recommended for patients with HCC if at least one of the following factors is present: unintentional weight loss of 10% or more from baseline over the past 6 months, body mass index <18.5 kg/m², or inadequate dietary intake (caloric intake <1500 kcal/day) to improve treatment outcomes and patient survival [107].

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

Comments: the purpose of nutritional support combined with exercise therapy is to maintain the patient's functional status and prevent the development of sarcopenia. Oral nutrition (sip feeding) is the preferred method of nutritional support. If oral intake is impossible or inadequate, a nasogastric tube or temporary gastrostomy must be placed.

The caloric intake of the diet should be 25–30 kcal per kg of body weight per day, and the protein dose should be 1.0–1.5 g per kg of body weight per day. Daily requirements for vitamins and micronutrients must be met. It is preferable to use ready-made formulas enriched with protein and omega-3 polyunsaturated fatty acids in a daily dose of at least 400 ml (of the prepared drink). When nutritional support is used for at least 7 days, the incidence of infectious complications and the duration of postoperative hospital stay are significantly reduced [108].

4.2 Rehabilitation in surgical treatment

4.2.1 Stage I rehabilitation

• Patients with HCC are recommended to start early enteral nutrition (on the 2nd postoperative day) guided by the general principles of nutritional support after abdominal surgeries to reduce the rate of complications and the duration of hospital stay [107].

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

Comments: the purpose of early patient mobilization combined with adequate nutritional support is to improve the patient's cardiorespiratory endurance, resulting in a decrease in the incidence of non-surgical complications and the duration of hospital stay.

4.2.2 Stage II rehabilitation

• Patients are recommended aerobic exercise with a gradual increase in intensity lasting up to 150 minutes per week, as well as resistance exercises (8–10 repetitions for major muscle groups) twice a week under the supervision of a physical therapy instructor to improve the patient's quality of life and accelerate social rehabilitation [110,111].

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

Comments: the goal of physical exercise is to restore cardiorespiratory endurance, which prevents the development of muscle weakness, the onset and progression of sarcopenia, improves the patient's quality of life, and accelerates social rehabilitation.

• Patients with HCC are recommended to undergo electrosleep therapy sessions according to standard methodology to improve quality of life [112].

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

Comments: the purpose of electrosleep sessions is to produce a pronounced sedative effect, which reduces manifestations of asthenic and depressive syndromes, decreases the intensity of headaches and manifestations of biliary dyskinesia, significantly improving the patient's quality of life.

4.2.3 Stage III rehabilitation

• Patients with HCC in remission are recommended regular home-based therapeutic exercises, starting with low-intensity aerobic exercise with a gradual increase to moderate-intensity aerobic exercise combined with resistance exercises for major muscle groups (15–20 min, 8–10 repetitions) twice a week to improve cardiorespiratory endurance and enhance quality of life [113].

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

Comments: the goal of therapeutic exercise is to ensure the preservation of muscle mass, improve cardiorespiratory endurance, enhance quality of life, and increase overall survival. The desired training time is at least 30 minutes per day at moderate intensity several (most) days a week, taking into account the presence and severity of complications from anticancer treatment.

4.3 Rehabilitation in chemotherapy

• Patients with HCC receiving chemotherapy are recommended home-based therapeutic exercise sessions including moderate-intensity aerobic exercise to improve cardiorespiratory endurance [114].

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

• If polyneuropathy develops, patients with HCC are recommended a multi-component rehabilitation program including balance training exercises, low-level laser therapy, low-frequency magnetic therapy, and transcutaneous electrical nerve stimulation to reduce the symptoms of polyneuropathy [115–118].

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

• Throughout the course of chemotherapy, patients with HCC are recommended nutritional support as indicated, in a regimen matching that of the preoperative stage, to preserve muscle mass [107].

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

Comments: nutritional support is necessary to preserve muscle mass, which, combined with feasible physical exercise, prevents an increase in chemotherapy toxicity.

5. Prevention and Dispensary Observation

Comments: the objective of follow-up care is early detection of disease progression after treatment completion in order to promptly perform surgical treatment of resectable metastatic lesions, ablation and/or chemoembolization of recurrent tumors, and timely initiation of medical antineoplastic therapy.

6. Organization of Medical Care

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

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

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

3) based on these clinical guidelines;

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

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

When a cancer is suspected or diagnosed, general practitioners, district general practitioners, general practice physicians (family doctors), medical specialists, and mid-level medical personnel shall refer the patient in the prescribed manner for consultation to an outpatient cancer center, a primary oncology office, or a primary oncology department of a medical organization to receive primary specialized health care.

Consultation at an outpatient oncological care center or a primary oncological office/department of a medical organization must be carried out no later than 5 working days from the date of issuing the referral for consultation. The oncologist of the outpatient oncological care center (or the oncologist of the primary oncological office/department, if no such center exists) shall organize the collection of biopsy (surgical) material, as well as the execution 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 collect biopsy (surgical) material or perform other diagnostic tests at the medical organization that houses the outpatient oncological care center (primary oncological office, primary oncological department), the attending physician shall refer the patient to an oncological dispensary or a medical organization providing medical care to patients with oncological diseases.

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

If a cancer is detected or suspected during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to cancer patients to determine management tactics and the need for additional specialized antineoplastic treatment methods.

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

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

Specialized, including high-tech, medical care is provided by oncologists, radiotherapists, and endovascular diagnostic and treatment physicians in an oncology clinic or medical organizations providing care to cancer patients that have a license, the necessary material and technical base, and certified specialists, in inpatient and day-care settings, and includes the prevention, diagnosis, and treatment of oncological diseases requiring special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing care to cancer patients, the tactics of medical examination and treatment are determined by a concilium of oncologists, endovascular specialists, and radiotherapists, involving other medical specialists if necessary. The decision of the medical concilium is formalized in a protocol, signed by the participants of the concilium, and entered into the patient's medical documentation.

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

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

1) presence of complications of an oncological disease requiring specialized emergency and urgent medical care;

2) presence of complications resulting from oncological treatment (surgery, radiation therapy, drug therapy, etc.).

Indications for planned hospitalization in a medical organization are:

1) the need to perform complex interventional diagnostic medical procedures requiring subsequent observation in a 24-hour inpatient unit or day hospital;

2) presence of indications for specialized antitumor treatment (surgical intervention, interventional radiology, radiation therapy, including contact, external beam, and other types, 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 specialized, including high-tech, medical care in a 24-hour or day hospital setting in the absence of treatment complications requiring drug correction and/or medical interventions in an inpatient setting;

2) refusal of the patient or their legal representative to receive specialized, including high-tech, medical care in an inpatient or day-hospital setting as determined by a medical board of an oncology healthcare facility, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting;

3) the need to transfer the patient to another medical organization with the appropriate profile of medical care.

The conclusion regarding the advisability of transferring the patient to a specialized medical organization is issued following a preliminary consultation based on the provided medical documents and/or a preliminary examination of the patient by specialist physicians of the medical organization to which the transfer is planned.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Natalia A. Falaleeva, MD, DSc, Head of the Department of Drug Treatment of Malignant Neoplasms, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

2. Tatev A. Agababyan, MD, PhD, Associate Professor, Head of the Department of Diagnostic Radiology, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

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

4. Valeriy V. Breder, MD, DSc, Head of the Department of Drug Treatment, Antitumor Drug Therapy Department No. 3, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

5. Eduard R. Virshke, MD, DSc, Head of the Laboratory of Interventional Radiology, Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

6. Vadim N. Dmitriev, MD, DSc, Head of the Day Hospital of Antitumor Drug Therapy, Oncologist at the Antitumor Drug Therapy Department, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

7. Vyacheslav N. Grinevich, MD, PhD, Head of the Department of Oncopathology, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

8. Ruslan A. Zukov, Chief Physician, A.I. Kryzhanovsky Krasnoyarsk Regional Clinical Oncology Dispensary.

9. Aisha G. Isaeva, MD, PhD, Senior Research Scientist, Department of Radiation and Surgical Treatment of Abdominal Diseases, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

10. Aleksandr A. Kirshin, MD, PhD, Deputy Chief Physician for Medical Affairs, Chief Freelance Transplantologist of the Ministry of Health of the Republic of Tatarstan, Professor M.Z. Sigal Republican Clinical Oncology Dispensary of the Ministry of Health of the Republic of Tatarstan.

11. Antonina V. Levshakova, MD, DSc, Head of the Computed and Magnetic Resonance Tomography Department, Radiologist, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

12. Bela M. Medvedeva, MD, DSc, Leading Research Scientist, X-ray Diagnostics Department, Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

13. Andrey V. Moiseenko, X-ray Endovascular Diagnostics and Treatment Physician, Surgical Department No. 2 (Abdominal Oncology and Interventional Radiological Diagnostic and Treatment Methods), A.M. Granov Russian Research Center of Radiology and Surgical Technologies of the Ministry of Health of the Russian Federation.

14. Aleksey A. Polikarpov, MD, DSc, Honored Doctor of Russia, Principal Research Scientist, Department of Interventional Radiology and Operative Surgery, Professor at the Department of Radiology, Surgery, and Oncology, A.M. Granov Russian Research Center of Radiology and Surgical Technologies of the Ministry of Health of the Russian Federation.

15. Artur P. Petrosyan, MD, PhD, Interventional Radiologist, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

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

17. Igor V. Pogrebnyakov, MD, PhD, Leading Research Scientist, Abdominal Oncology Department No. 2 (Hepato-Pancreato-Biliary Tumors), N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

18. Danil V. Podluzhny, MD, PhD, Head of the Liver and Pancreas Tumors Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

19. Igor V. Sagaydak, MD, DSc, Professor, Leading Research Scientist, Abdominal Oncology Department No. 2 (Hepato-Pancreato-Biliary Tumors), N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

20. Maxim Ya. Smolyarchuk, Radiation Oncologist, Research Scientist, Department of Radiosurgical Treatment with Open Radionuclides, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

21. Aleksey V. Chzhao, MD, DSc, Professor, Deputy Director for Research, A.V. Vishnevsky Institute of Surgery.

Healthcare Organization Section:

1. Fomenko Yury Alexandrovich, PhD in Medicine, Deputy General Director for Clinical and Expert Work, National Medical Research Center for Oncology of the Russian Ministry of Health.

2. Ivanov Sergey Anatolyevich, MD, PhD, Professor, Corresponding Member of the RAS, Honored Physician of the RF, Director, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Center of Radiology of the Russian Ministry of Health, Chief freelance Oncologist of the Central Federal District of the Russian Ministry of Health.

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

4. Gevorkyan Tigran Gagikovich, Deputy Director for the Implementation of Federal Projects, N.N. Blokhin National Medical Research Center for Oncology of the Russian Ministry of Health.

5. Komarov Yury Igorevich, PhD in Medicine, Deputy Director for Organizational and Methodological Work, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1) oncologists;

2) surgeons;

3) radiation oncologists;

4) cardiovascular surgeons;

5) medical students, residents, and postgraduate students.

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

Grading system for levels of evidence for diagnostic methods (diagnostic interventions)

Grading system for levels of evidence for prevention, treatment and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Grades of Recommendation Scale for Prevention, Diagnostic, Treatment, and Rehabilitation Methods (Preventive, Diagnostic, Therapeutic, Rehabilitation Interventions)

Procedure for updating clinical guidelines

The guideline updating mechanism provides for their systematic revision at least once every 3 years, as well as upon the emergence of new evidence-based data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Figure A1. Barcelona Clinic Liver Cancer staging system for hepatocellular carcinoma [7]. OS – overall survival; ECOG – ECOG performance status; TACE – transarterial chemoembolization

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

Table 2. Drug treatment regimens for hepatocellular carcinoma

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Recommendations for primary prevention of hepatocellular carcinoma

The main risk factor for the development of liver cancer is chronic liver inflammation resulting from various damaging factors: chronic viral hepatitis B and C, alcohol consumption and other toxic substances, carbohydrate and fat metabolism disorders, and cirrhosis of various etiologies. The combination of several risk factors increases the probability of developing primary liver cancer. Vaccination against viral hepatitis B is a crucial preventive measure. Effective antiviral therapy for chronic hepatitis C reliably reduces the likelihood of developing liver cancer.

Recommendations for chemotherapy complications

In case of chemotherapy complications, it is necessary to contact an oncologist (chemotherapist).

1. If body temperature rises to +38°C and above, start taking antibiotics as prescribed by the oncologist.

2. In case of stomatitis:

• mechanically and thermally sparing diet;

• frequent (hourly) mouth rinsing with decoctions of chamomile, sage, oak bark, lubricating the mouth with sea buckthorn (peach) oil;

• oral cavity care as recommended by the oncologist.

3. In case of diarrhea:

• exclude fatty, spicy, smoked, sweet, dairy foods, and fiber. Lean meat, flour products, fermented dairy products, rice water, and abundant fluids are permitted;

• take medications as prescribed by your oncologist.

4. In case of nausea, take medications as prescribed by your oncologist.

5. If side effects specific to continuous targeted therapy develop—arterial hypertension, appearance of cracks on the skin of hands and feet, recurrent diarrhea, severe weakness—disposition of the drug should be stopped and the attending physician should be contacted immediately. Information for patients receiving therapy with monoclonal antibodies blocking CTLA4 and/or PD1/PD-L1

Timely communication with your attending physician and nurse regarding your health status is an important part of helping the medical team protect you as completely as possible during your treatment.

It is very important that any symptoms (side effects) associated with CTLA4 and/or PD1 blocker therapy are identified and managed at their very first appearance; this will help prevent them from progressing into more severe forms.

CTLA4 blockers and/or PD1/PD-L1 blocking monoclonal antibodies are designed to help your body's immune system fight the tumor process. The most common side effects you may encounter during treatment are the result of high immune system activity. Such side effects are called immune-mediated and differ from the side effects you may observe with other types of cancer treatment.

The side effects you may experience usually occur in the first 12 weeks of treatment, but may also appear later.

It is very important that you inform your attending physician of any symptoms that appear during treatment with CTLA4 and/or PD1/PD-L1 blockers. Recognizing side effects at early stages enables your attending physician to immediately initiate appropriate therapy and prevent side effects from progressing into more severe forms.

If after treatment with CTLA4 blockers and//or PD1/PD-L1 blocking MAbs you experience any of the symptoms listed below, please inform your attending physician immediately.

Possible side effects of therapy with CTLA4 and/or PD1/PD-L1 blockers:

• increased frequency of bowel movements (>2 times per day) or any nocturnal diarrhea, any stool containing mucus and blood;

• abdominal pain or chills, as well as pain requiring medical intervention;

• red, painful eyes or yellowish coloration of the whites of the eyes, blurred vision, inflammation or swelling of the eyes;

• yellowing or redness of the skin, itchy rash, skin sensitivity to sunlight;

• onset of cough or shortness of breath;

• fatigue or drowsiness;

• difficulty concentrating or confusion;

• headache, body aches, or pain at the tumor site;

• fever (increase in body temperature up to +38°C and above);

• sudden decrease or increase in body weight;

• onset of erectile dysfunction or loss of interest in intimate life.

Please pay special attention to any changes in bowel movements. Record the number of bowel movements every day. If you have diarrhea, try to describe it using one of the terms below and determine the level of urgency for your specific case:

– loose stool;

– watery;

– painful;

– bloody;

– mucoid.

Diarrhea may not always present as loose stool. An increased frequency of bowel movements per day, even with hard stool, can potentially indicate a problem.

Important: side effects may occur from 1 week to several months after starting treatment with CTLA-4 and/or PD-1/PD-L1 blockers. If you experience any of the above symptoms, immediately report them to your attending physician or nurse.

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

Appendix G1.

a. Child-Pugh liver function grading scale

Russian name: Child-Pugh classification of the severity of liver cirrhosis

Original name: Child-Pugh classification

Source (official developer website, validation publication):

1. Cholongitas E. et al. Systematic review: The model for end-stage liver disease - Should it replace Child-Pugh’s classification for assessing prognosis in cirrhosis? // Alimentary Pharmacology and Therapeutics. 2005. Vol. 22, № 11–12. P. 1079–1089.

2. Child C.G., Turcotte J.G. Surgery and portal hypertension // The Liver and Portal Hypertension. Philadelphia: Saunders, 1964. 50–58 p.

3. Pugh R.N.H. et al. Transection of the oesophagus for bleeding oesophageal varices // Br. J. Surg. 2005. Vol. 60, № 8. P. 646–649.

Type: rating scale.

Purpose: to determine the severity of liver function impairment.

Content:

Notes: chronic liver damage (dysfunction) is classified as Child-Pugh class A, B, or C, depending on the total score obtained for each parameter. Class A: 5–6 points, class B: 7–9 points, and class C: 10–15 points.

b. ALBI score

Russian name: ALBI score – liver function impairment class

Original name: ALBI-score

Source (official developer website, validation publication):

1. Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma: A new evidence-based approach-The ALBI grade. J Clin Oncol 2015;33:550-558.

2. Oikonomou T, Goulis L, Doumtsis P, et al. ALBI and PALBI grades are associated with the outcome of patients with stable decompensated cirrhosis. Ann Hepatol 2019;18:126-136. https://www.ncbi.nlm.nih.gov/pubmed/31113581.

Type: rating scale.

Purpose: to determine the severity of liver function impairment.

Content: calculated by the formula: [log10 bilirubin (μmol/L) x 0.66 + [albumin (g/L x -0.085]. The ALBI grade is defined as:

grade 1 ≤ -2.60 – well-preserved liver function; grade 2 > -2.60 to ≤ -1.39 moderate liver dysfunction; grade 3 > -1.39 – severe liver dysfunction.

Appendix G2. WHO/ECOG performance status scale

Russian title: WHO/ECOG performance status scale.

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

Source (official developer website, validation publication):

1. https://ecog-acrin.org/resources/ecog-performance-status.

2. Oken M.M., Creech R.H., Davis T.E. Toxicology and response criteria of the Eastern Cooperative Oncology Group // Am. J. Clin. Oncol. Cancer Clin. Trials. 1982. Vol. 5, № 6. P. 649–655.

Type: rating scale.

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

Content:

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

Appendix G3. Karnofsky performance scale

Russian title: Karnofsky Performance Scale.

Original title: Karnofsky Performance Status.

Original publication:

Karnofsky DA B.J.H. The clinical evaluation of chemotherapeutic agents in cancer. Evaluation of Chemotherapeutic Agents. // Columbia Univ. Press. 1949. P. 191–205.

Type: rating scale.

Purpose: to assess the patient's level of functioning in terms of their ability to care for themselves, daily activity, and physical capability (walking, working, etc.).

Content:

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

Appendix G4. Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Russian title: Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

Original name: Response Evaluation Criteria in Solid Tumors 1.1.

Original publication:

Eisenhauer E.A. et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) // Eur. J. Cancer. 2009. Vol. 45, № 2. P. 228–247.

Type: rating scale.

Purpose: evaluation of response to chemotherapy.

Content, key, and template in Russian are presented in methodological guidelines No. 46 of the Scientific and Practical Center of Medical Radiology of the Moscow Healthcare Department and are available at http://medradiology.moscow/d/1364488/d/no46_2018_recist_11.pdf. This document is the property of the Moscow Healthcare Department and may not be reproduced or distributed without appropriate permission.

Appendix G5. Criteria for tumor response evaluation to treatment (mRECIST)

Russian title: Modified Response Evaluation Criteria in Solid Tumors (mRECIST).

Original name: Modified Response Evaluation Criteria in Solid Tumors.

Original publication:

Lencioni R., Llovet J.M. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma // Seminars in Liver Disease. 2010. Vol. 30, № 1. P. 52–60.

Type: rating scale.

Purpose: evaluation of response to targeted therapy and locoregional treatment of HCC.

Assessment is performed using CT or MRI, exclusively in the arterial phase of scanning. The longest diameter of the lesion is measured in the portion that shows the most intense post-contrast enhancement in the arterial phase.

Evaluation criteria:

• Complete Response (CR) – Disappearance of any intratumoral arterial enhancement in all target lesions.

• Partial Response (PR) – At least a 30% decrease in the sum of diameters of target lesions, assessed in the arterial phase of contrast enhancement.

• Progressive Disease (PD) – An increase of 20% or more in the sum of diameters of target lesions, assessed in the arterial phase of contrast enhancement.

• Stable Disease (SD) – Anything else.