Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition)
1 Overview
Primary liver cancer is currently the fourth most common malignant tumor and the second cause of tumor death in mainland China, which seriously threatens the life and health of people in mainland China [1-3]. Primary liver cancer mainly includes hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and mixed hepatocellular carcinoma - cholangiocarcinoma (cHCC-CCA) three different pathological types, the three in the pathogenesis, Biological behavior, histopathology, treatment, and prognosis vary widely, with HCC accounting for 75 to 85 percent and ICC accounting for 10 to 15 percent [4]. "Liver cancer" in this guideline refers only to HCC.
In order to further standardize the diagnosis and treatment of liver cancer in mainland China, in June 2017, the former National Health and Family Planning Commission promulgated the "Specifications for the Diagnosis and Treatment of Primary Liver Cancer (2017 Edition)", which was updated by the National Health Commission in December 2019. The "Primary Liver Cancer Diagnosis and Treatment Specifications (2019 Edition)" reflects the situation of liver cancer diagnosis and multidisciplinary comprehensive treatment and research in mainland China at that time, and played an important role in standardizing the diagnosis and treatment behavior of liver cancer, improving the prognosis of liver cancer patients, ensuring medical quality and medical safety, and optimizing medical resources.
Since the release of the "Specifications for the Diagnosis and Treatment of Primary Liver Cancer (2019 Edition)", there has been a lot of high-level evidence in the diagnosis, staging and treatment of domestic and extrinsic liver cancer that conforms to the principles of evidence-based medicine, especially the research results adapted to China's national conditions. To this end, the National Health Commission commissioned the Oncology Branch of the Chinese Medical Association, together with the Liver Cancer Professional Committee of the Chinese Anti-Cancer Association, the Ultrasound Medicine Branch of the Chinese Medical Association, the Surgeons Branch of the Chinese Medical Doctor Association and the Interventional Physicians Branch of the Chinese Medical Doctor Association to organize multidisciplinary experts in the field of liver cancer nationwide, combined with the latest practice of clinical diagnosis and treatment and research of liver cancer, to revise and update the "Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition)", aiming to promote the implementation and achieve the "Healthy China 2030" Planning Outline. The goal of improving 5-year survival rates for patients with middle liver cancer is 15%.
The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology is currently the most widely used evidence evaluation and recommendation grading system [5]. The GRADE system consists of two parts, the first part is the evaluation of evidence, according to the risk of bias, inconsistencies, indirectness, inaccuracy and publication bias in the evidence, the GRADE system divides the quality of evidence into high, medium, low, and very low levels [6].
The second part is the grading of recommendations, and the GRADE system considers the balance of advantages and disadvantages of medical interventions, the quality of evidence, values and preferences, and cost and resource consumption to formulate recommendations, and divides the recommendations into two types: strong recommendations and weak recommendations (conditional recommendations) [7]. The greater the difference in the pros and cons of medical intervention, the higher the quality of the evidence, the clearer and more convergent values and preferences, and the smaller the cost and resource consumption, the more strong recommendation should be considered. Conversely, weak recommendations (conditional recommendations) should be considered. The evidence-based evidence level assessment in this guide refers to the guidelines for grade grading above and uses the OCEBM Levels of Evidence 2011 edition of Oxford Evidence As an adjunct to specifically implement evidence grading (Appendix 1).
In the method of converting from evidence to recommendation, the expert group mainly referred to the above-mentioned GRADE guidelines for the grading of recommendations, but at the same time combined with the grading scheme of the ASCO guidelines [8] to make corresponding modifications to the grading of recommendations (Appendix 2). Finally, the recommendation strength is divided into three levels, which are strong recommendation, moderate recommendation, and weak recommendation. Strong recommendations represent a high level of confidence that the recommendation reflects best clinical practices and should be adopted by the vast majority, if not all, of target users. Moderate recommendation represents a moderate degree of confidence that the recommendation reflects best clinical practice, and most target users will adopt the recommendation, but care should be taken to consider joint doctor-patient decision-making during implementation. If the recommendation represents a panel of experts who have some confidence that the recommendation reflects best clinical practice, it should be conditionally applied to the target group, emphasizing joint decision-making between doctors and patients.
2 Screening and diagnosis
Screening and monitoring of people at high risk of liver cancer
Screening and monitoring of people at high risk of liver cancer contributes to the early detection, early diagnosis, and early treatment of liver cancer, and is key to improving the efficacy of liver cancer [9]. The rapid and convenient identification of high-risk groups of liver cancer is the premise of implementing large-scale liver cancer screening, and the hierarchical assessment of liver cancer risk in the population is the basis for formulating different liver cancer screening strategies. In mainland China, people at high risk of liver cancer mainly include: Hepatitis B virus (HBV) and/or Hepatitis C virus (HCV) infection, excessive alcohol consumption, non-alcoholic steatohepatitis, cirrhosis of the liver caused by other causes, and a family history of liver cancer, especially men > 40 years of age.
Currently, although anti-HBV and anti-HCV therapy can significantly reduce the risk of liver cancer, it is not possible to completely avoid it [10]. The age-Male-AlBi-Platelets score, which is developed by mainland scholars for a variety of chronic liver diseases and liver cancer risk assessment models of various ethnic groups, can conveniently divide liver disease populations into low-risk (0-50 points), medium-risk (50-60 points) and high-risk (60-100 points) groups, and the annual incidence of liver cancer in each group is 0-0.2%, 0.4%-1% and 1.6%-4%, respectively, which helps to determine the high-risk groups of liver cancer [11] (evidence level 2, recommendation B). Early screening for liver cancer with liver ultrasound imaging and serum alpha-fetoprotein (AFP) is recommended for high-risk populations at least every six months [9] (evidence level 2, recommendation A). By realizing the new model of integrated screening in communities and hospitals [12], it is necessary to screen exhaustively and treat early.
Imaging tests for liver cancer
Various imaging tests have their own characteristics, and comprehensive application, complementary advantages, and comprehensive assessment should be emphasized.
1. Ultrasound imaging
Ultrasound imaging has the advantages of convenient, real-time, non-invasive and non-radiation radiation, and is the most commonly used liver imaging method in clinical practice. Conventional grayscale ultrasound imaging can detect intrahepatic mass lesions early and sensitively, identify them as cystic or substantial, and initially determine whether they are benign or malignant. At the same time, grayscale ultrasound imaging can comprehensively screen other organs in the liver or abdominal cavity for metastases, intrahepatic vascular and bile duct violations. Color Doppler blood flow imaging can observe the blood supply status of the lesion, assist in judging the benign and malignant nature of the lesion, show the adjacent relationship between the lesion and the important blood vessels in the liver, and whether there is a violation of the intrahepatic blood vessels, and can also preliminarily judge the efficacy of local treatment of liver cancer.
Ultrasonography can dynamically observe changes in blood flow perfusion of liver tumors in real time, differentially diagnose liver tumors of different natures, use small lesions that can sensitively detect occult lesions during surgery, guide local treatment in real time, and evaluate the efficacy of local treatment of liver cancer after surgery [13-16] (evidence level 3, recommendation A). Ultrasound combined image navigation technology provides an effective technical means for the precise localization and ablation of liver cancer, especially occult liver cancer that cannot be visualized by conventional ultrasound imaging [13,17] (evidence level 4, recommendation B). Ultrasound shear wave elastography quantitatively assesses the degree of tissue hardness of liver tumors and the degree of fibrosis/sclerosis of the surrounding liver parenchyma, providing useful information for planning a reasonable liver cancer treatment regimen [18] (evidence level 4, recommendation B). The combined application of multimodal ultrasound imaging technology has played an important role in the accurate preoperative diagnosis, intraoperative localization and postoperative evaluation of liver cancer.
2. CT and MRI
Dynamic enhanced CT, multiparameter MRI scan is the imaging test of choice for definitive diagnosis of patients with liver ultrasound and/or serum AFP screening abnormalities. CT/MR (gadolinium injection glucosamine/gadolinium meglumine) dynamic enhancement phase 3 scans include: advanced arterial (portal vein begins to strengthen; usually scanned about 35s after contrast medium injection), portal phase (portal vein is fully strengthened; hepatic vein visible contrast medium filling; liver parenchyma usually peaks; usually 60 to 90s scan after contrast medium injection), delayed period (portal vein and hepatic vein are strengthened but lower than the portal phase; liver parenchyma is visible but less than the portosystemic phase; usually scanned 3min after contrast medium injection).
Hepatocyte-specific magnetic resonance contrast agents (disodium gadotropate, Gd-EOB-DTPA) phase 4 scans include: advanced arterial (ditto), portal phase (ditto), migration phase (liver vascular and hepatic parenchymal signal intensity is the same; liver strengthening is produced by intracellular and extracellular synergistic action; usually scan after injection of Gd-EOB-DTPA 2 to 5 min), hepatobiliary specific phase (liver parenchymal signal is higher than hepatic vessels; contrast media is excreted through the bile duct system; usually in the injection of disodium gadolinate Scan after 20min).
At present, in addition to the clinical diagnosis and staging of liver cancer, hepatic CT scan and dynamic enhanced scanning are also used to evaluate the efficacy of local treatment of liver cancer, especially to observe the iodine oil deposition status after transcatheter arterial chemoembolization (TACE) has advantages. Preoperative CT-based radiomics techniques can also be used to predict the efficacy of first TACE treatment [19]. At the same time, with the help of CT post-treatment technology, three-dimensional vascular reconstruction, liver volume and liver tumor volume measurement, lung and bone tissue metastases can be evaluated, which has been widely used in clinical practice.
Liver multiparameter MRI has the advantages of no radiation effect, high tissue resolution, multi-faceted multi-sequence multi-parameter imaging, and comprehensive imaging technology capabilities with morphological binding function (including diffusion-weighted imaging, etc.), which has become the preferred imaging technology for clinical detection, diagnosis, staging and efficacy evaluation of liver cancer. Multiparametric MRI is superior to dynamic enhanced CT [20,21] in terms of detection and diagnostic capacity for liver cancer ≤2.0 cm in diameter (evidence level 1, recommendation A). Multiparametric MRI has the advantage of dynamic enhanced CT in evaluating whether liver cancer invades the portal vein, the hepatic vein trunk and its branches, and lymph node metastases in the abdominal or retroperitoneal space. When using multiparameter MRI scans to evaluate the efficacy of local treatment of liver cancer, it is recommended to use modified response evaluation criteria in solid tumor (mRECIST) plus T2-weighted imaging and diffusion-weighted imaging for comprehensive judgment.
Imaging diagnosis of liver cancer is based primarily on the "fast-forward, fast-out" approach to dynamic enhanced scanning [22-24] (evidence level 1, recommendation A). Dynamic enhancement CT and multiparameter MRI liver tumors in the arterial phase (mainly in the advanced arterial stage) show uniform or uneven significant intensification, and portal and/or delayed liver tumors are less intense than the liver parenchyma. "Fast forward" is non-circular reinforcement, and "fast-out" is non-peripheral clearance. "Fast forward" is observed in the late arterial stage, and "fast out" is observed in the portal phase and delayed phase. Gd-EOB-DTPA can only be observed for signs of "quick out" in the portal phase, and "fast out" signs during the transitional phase and hepatobiliary specific phases can be used as auxiliary signs of malignancy.
Gd-EOB-DTPA enhanced MRI shows that the arterial phase of hepatic tumors is significantly strengthened, the portal artery phase is strengthened lower than the liver parenchyma, and the hepatobiliary-specific phase is often markedly low-signaled. Small liver cancers with better differentiation in 5 to 12 percent may show a slightly higher signal of absorption of contrast media in the hepatobiliary-specific phase [25].
Multiparameter MRI scans of liver cancer, particularly those used to diagnose liver cancer with a tumor diameter of ≤2.0 cm/< 1.0 cm, emphasize the need to combine other signs (e.g., envelope-like intensification, medium signal in T2-weighted imaging, and diffusion restriction, etc.) and over-threshold growth [50% (inclusive) increase in the maximum diameter of the lesion within 6 months] [26] (Evidence Level 3, Recommendation A). Envelope-like strengthening is defined as smooth, uniform, well-defined, most or all-encompassing lesions, particularly in the portal, delay, or transition phases.
Gd-EOB-DTPA enhanced MRI in combination with hepatobiliary-specific phase hyposignia, arterial phase strengthening, and diffusion restriction can significantly improve the diagnostic sensitivity of liver cancer < 1.0 cm in diameter [27-31] (evidence level 2, recommendation B), especially in patients with cirrhosis, and is also helpful in differentiating precancerous lesions such as high-grade dysplastic nodules (HGDN) [32]. 3, recommended B).
Establishing ensemble models based on clinical data mining based on CT and/or MRI information for liver cancer can help improve clinical decision-making (patient treatment options, efficacy evaluation, and prediction) [33]. For preoperative prediction of microvascular invasion (MVI) of liver cancer, imaging signs are specific but low sensitivity, and line line diagrams and radioomic models are possible breakthrough points for preoperative prediction of MVI [34-36] (evidence level 3, recommendation B).
3. Digital subtraction angiography
Digital subtraction angiography (DSA) is a minimally invasive test that uses a selective or hyperselective hepatic artery for DSA. This technique is more used in the treatment of local treatment of liver cancer or the treatment of spontaneous rupture and bleeding of liver cancer. DSA tests can show liver tumor blood vessels and liver tumor staining, and can also clearly show the number, size and blood supply of liver tumors.
4. Nuclear medicine imaging examination
(1) Positron emission tomography-CT (PET-CT), fluorine-18-fluorodeoxyglucose (18F-fluorodeoxyglucose, 18F-FDG) PET-CT full-body imaging Advantages are:
(1) Tumor staging can be comprehensively evaluated for lymph node metastasis and metastases of distant organs through a single examination [37,38] (evidence level 1, recommendation A);
(2) Restaging, because PET-CT functional images are not affected by anatomy, can accurately show recurrent metastases after anatomical changes or complex anatomical parts [39] (evidence level 3, recommendation B);
(3) More sensitive and accurate evaluation of the efficacy of targeted drugs that inhibit tumor activity [40,41] (evidence level 3, recommendation A);
(4) Guide the delineation of biological target areas of radiotherapy and determine the site of puncture biopsy [39];
(5) Evaluation of the degree of malignancy and prognosis of tumors [42-45] (evidence level 1, recommendation B). PET-CT has limited diagnostic sensitivity and specificity for liver cancer, and can be used as an adjunct and supplement to other imaging tests, and has advantages in the staging, restaging and efficacy evaluation of liver cancer. Imaging agents such as carbon-11-labeled acetate (11C-acetate) or choline (11C-choline) can improve sensitivity to the diagnosis of highly differentiated liver cancer and complement 18F-FDG PET-CT imaging [46,47].
(2) Single photon emission computed tomography-CT (SPECT-CT): SPECT-CT has gradually replaced SPECT as the mainstream equipment for single-photon imaging in nuclear medicine, selecting the lesions found by the whole body plane imaging, and then performing local SPECT-CT fusion imaging, which can obtain SPECT and diagnostic CT images of the lesion site at the same time. Diagnostic accuracy was significantly improved [48] (evidence level 3, recommendation A).
Positron emission tomography-MRI (PET-MRI): A single PET-MRI examination can obtain both anatomical and functional information of the disease, improving the sensitivity of liver cancer diagnosis [49] (evidence level 4, recommendation C).
Hematologic molecular marker of liver cancer
Serum AFP is currently commonly used and important indicator for diagnosing liver cancer and monitoring efficacy. Serum AFP ≥ 400 μg/L, which is highly suggestive of liver cancer after exclusion of pregnancy, chronic or active liver disease, germ gonadal embryonic tumors, and gastrointestinal tumors, while mildly elevated serum AFP should be combined with imaging or ambulatory observation, and comparative analysis with changes in liver function to help diagnose. Abnormal prothrombin (Protein induced by vitamin K absence/antagonist-II., PIVKAII.;D es-gamma carboxyprothrombin (DCP), plasma free microRNAs (microRNAs) [50], and serum lens culinaris agglutinin-reactive Fraction of AFP, AFP-L3) can also be used as a marker for early diagnosis of liver cancer, particularly in serum AFP-negative populations (evidence level 1, recommendation A). The GALAD model based on sex, age, AFP, PIVKAII., and AFP-L3 has a sensitivity and specificity of 85.6% and 93.3%, respectively, in the diagnosis of early liver cancer, which is helpful for the early diagnosis of AFP-negative liver cancer [51] (evidence level 2, recommendation A). At present, an optimized GALAD-like model based on large sample data from Chinese populations is used for the early diagnosis of liver cancer. The sensitivity and specificity of the seven miRNA-based detection reagents and the diagnosis of liver cancer were 86.1% and 76.8%, respectively, and the sensitivity and specificity for AFP-negative liver cancer were 77.7% and 84.5%, respectively [50] (evidence level 2, recommendation A). For an introduction to other novel hematologic molecular markers for early diagnosis and efficacy evaluation of liver cancer, see Appendix 3.
Puncture biopsy of liver cancer
Patients with hepatic mass lesions with typical hepatic cancer imaging features that meet the criteria for clinical diagnosis of liver cancer typically do not require diagnostic biopsy of the liver lesion [23,52-54] (evidence level 1, recommendation A), especially in patients with hepatic cancer with surgical indications. In patients with liver cancer who can be surgically removed or prepared for liver transplantation, preoperative puncture biopsy of liver lesions is not recommended to reduce the risk of rupture, bleeding, and dissemination of liver tumors. For hepatic mass lesions that lack the imaging features of typical liver cancer, puncture biopsy of the liver lesion can obtain a definitive pathological diagnosis. Puncture biopsy of liver lesions can determine the nature of the lesion and the molecular classification of liver cancer [59], and provide valuable information for clarifying the cause of liver disease, guiding treatment, judging prognosis, and conducting research, so the need for puncture biopsy should be comprehensively assessed based on the benefits, potential risks, and physician experience of patients with liver lesion biopsy.
Puncture biopsy of liver lesions is usually performed under ultrasound or CT guidance, and lesion tissue can be obtained using 18 G or 16 G liver puncture empty core needle biopsy. The main risk is the possibility of bleeding and implant metastasis of the tumor needle. Therefore, platelets and coagulation should be checked preoperatively, and puncture biopsy of liver lesions should be avoided in patients with severe bleeding tendencies. The puncture path should pass through normal liver tissue as much as possible, avoiding direct puncture of nodules on the surface of the liver. The puncture site should be selected for imaging examination showing the tumor active inside and next to the tumor, and the completeness of the material should be observed with the naked eye after taking the material to improve diagnostic accuracy. In addition, due to various factors such as the size of the lesion and the depth of the site, there is also a certain false negative rate in the pathological diagnosis of puncture of liver lesions, especially for lesions with a diameter of ≤2 cm, the false negative rate is high. Therefore, a negative result of a puncture biopsy of the liver lesion does not completely exclude the possibility of liver cancer, and it still needs to be observed and followed up regularly. Patients with too few biopsy tissue samples, negative pathological results, but high clinical suspicion of liver cancer may be repeatedly performed with a liver lesion aspiration biopsy or close follow-up.
Discussion of key points
(1) With the help of liver ultrasound imaging combined with serum AFP for early screening of liver cancer, it is recommended that high-risk groups undergo examinations at least once every 6 months.
(2) Dynamic enhanced CT and multiparameter MRI scans are the preferred imaging tests for the definitive diagnosis of patients with liver ultrasound imaging and/or serum AFP screening abnormalities.
(3) The imaging diagnosis of liver cancer is mainly based on the reinforcement method of "fast-forward and fast-out".
(4) Liver multiparameter MRI examination is the preferred imaging technology for clinical diagnosis, staging and efficacy evaluation of liver cancer.
(5) PET-CT scan is helpful for staging and efficacy evaluation of liver cancer.
(6) Serum AFP is a common and important indicator for the diagnosis of liver cancer and the monitoring of efficacy. For serum AFP-negative people, early diagnosis can be made with the help of PIVKAII., miRNA detection kits, AFP-L3, and GALAD-like models.
(7) Patients with hepatic mass lesions with typical imaging characteristics of liver cancer, patients who meet the clinical diagnostic criteria for liver cancer usually do not need puncture biopsy for the purpose of diagnosis.
Pathological diagnosis of liver cancer
1. Liver cancer pathological diagnostic terminology
Primary liver cancer: refers to malignant tumors originating from hepatocytes and intrahepatic bile duct epithelial cells, mainly including HCC, ICC and cHCC-CCA.
(1) HCC: refers to malignant tumors that occur in hepatocytes. The pathological diagnosis of "hepatocellular carcinoma" or "hepatocellular carcinoma" is not recommended.
(2) ICC: refers to the malignant tumor of the epithelial cells lined with branches of the bile ducts in the liver, and adenocarcinoma is the most common. Histologically can be divided into: (1) bold cast type: originating from the larger bile ducts above the lobular septal duct to the adjacent hepatic portal area, the glandular duct caliber is large and irregular; (2) small bile duct type: originating from the lobular septal bile duct and below the small bile duct or fine bile duct, the glandular duct caliber is small and more regular, or can be a solid thin cord with lumen closure. Studies have shown that the biological behavior and genotypic characteristics of the above two subtypes of ICC are also different, and the clinical outcome of patients with small bile duct type is better than that of bold cast.
The clinical and pathological significance of molecular typing of HCC and ICC is at the research and demonstration stage, but in recent years, studies have shown that EBV-related ICC has special clinical pathology, immune microenviral and molecular characteristics, has a good prognosis and a good benefit from immune checkpoint therapy, and is expected to become a new subtype [55]; while the high expression of propylose phosphate isomerase 1 in ICC tissues is a useful indicator for assessing the risk of postoperative recurrence [56]. The 2019 edition of the WHO Classification of Tumors of the Digestive System no longer recommends the use of the pathological diagnostic names "Cholangiocellular carcinoma and Cholangiolocellular carcinoma" for ICC [57]. The general material and microscopic examination requirements of ICC are mainly referred to HCC.
(3) cHCC-CCA: refers to the simultaneous occurrence of HCC and ICC two tissue components in the same tumor nodule, excluding collision carcinoma. Although some scholars have suggested that the proportion of the two tumor components ≥ 30% respectively as the pathological diagnostic criteria for cHCC-CCA [58], there is no internationally unified pathological diagnostic standard for the proportion of HCC and ICC tumor components in cHCC-CCA. To this end, it is recommended that the proportion of the two tumor components be marked in the pathological diagnosis of cHCC-CCA for reference when clinically evaluating the biological characteristics of tumors and formulating diagnosis and treatment plans.
2. Specifications for pathological diagnosis of liver cancer
The pathological diagnosis specification for liver cancer consists of specimen management, specimen collection, pathological examination, and pathological reporting [58,59].
(1) Key points of specimen treatment: (1) The surgeon should clearly mark the location, type and quantity of the specimen sent for examination on the pathological examination application form, and the surgical margin and important lesions can be marked with dye dyeing or sutures; (2) as far as possible within 30 minutes of the in vitro, the tumor specimen will be delivered to the pathology department intact and fixed. Tissue banking should be carried out under the guidance of the department of pathology to ensure the accuracy of the material, and should first meet the needs of pathological diagnosis; (3) 4% neutral formaldehyde (10% neutral formalin) solution fixed for 12-24 h.
(2) Key points of specimen extraction: The surrounding area of liver cancer is a representative area of tumor biological behavior. To this end, a 7-point baseline feeding method (Figure 1) is required to take materials at the junction of cancer and paracancertic liver tissue at the clock bits 12, 3, 6 and 9 points of the tumor; at least 1 piece of material inside the tumor; and 1 piece of liver tissue each ≤ 1 cm (near carcinoma) and > 1 cm (paracarcinal side) from the tumor edge. For small liver cancer with a single tumor with a maximum diameter of ≤3 cm, all materials should be taken for examination. The actual location and quantity of materials to be taken must also be considered in terms of the diameter and number of tumors [60,61] (evidence level 3, recommendation A).
3. Key points of pathological examination of liver cancer
(1) General specimen observation and description [62]: All surgical specimens submitted for examination are comprehensively observed, focusing on the size, quantity, color, texture, relationship with blood vessels and bile ducts, envelope condition, peripheral liver tissue lesions, cirrhosis type, distance from tumor to incision margin and incision margin.
(2) Microscopic observation and description [62]: For a comprehensive observation of all the tissues taken from the material, the pathological diagnosis of liver cancer can refer to the 2019 edition of the WHO Classification of Tumors of the Digestive System[58], focusing on the following: The degree of differentiation of liver cancer: The internationally commonly used Edmondson-Steiner ivy (I.~IV.) classification method or the who recommended high-, medium-low differentiation can be used. Histological morphology of liver cancer: common thin beam type, coarse beam type, pseudodenophal tube type and mass type, etc.; special subtypes of liver cancer: such as fibrous laminar type, sclerosis type, transparent cell type, fat-rich type, giant beam type, color-like type, neutrophil-rich type, lymphocyte-rich and undifferentiated type, etc.; tumor necrosis (such as after hepatic artery chemotherapy embolization), the scope and degree of lymphocyte infiltration and interstitial fibrosis; liver cancer growth mode: including peri-cancer invasion, enveloping invasion or breakthrough, MVI and satellite nodules Assessment of chronic liver disease: Liver cancer is often accompanied by different degrees of chronic viral hepatitis or cirrhosis, and the simpler Scheuer scoring system and histological grading and staging criteria for chronic viral hepatitis in China are recommended [63-65].
(3) MVI diagnosis: MVI refers to the presence of cancer cell nests in the vascular lumen lined with endothelial cells under the microscope [66], and liver cancer is most commonly invaded by portal vein branches (including intracapsular blood vessels), and lymphatic vessels can be violated in ICC. Pathological grading methods: M0: no MVI was found; M1 (low-risk group): ≤ 5 MVI and all occurred in paracarcinal tissue (≤ 1 cm); M2 (high-risk group): > 5 MVI, or MVI occurred in paracular hepatic tissue (> 1cm）[67]。 MVI and satellite foci can be seen as different stages of the evolution of the intrahepatic metastases process of liver cancer, and can be counted together in MVI pathological grading when satellite nodules or satellite foci in paracancertic tissue or satellite foci are indistinguishable from MVI. MVI is an important reference for assessing the risk of hepatic cancer recurrence and for selecting treatment options [58,59,68-70] and should be used as an indicator of routine histopathology (evidence level 2, recommendation A).
4. Immunohistochemical examination
The main objectives of hepatocellular carcinoma immunohistochemistry are: (1) the distinction between benign and malignant tumors of hepatocytes; (2) the differentiation between HCC and ICC and other special types of liver tumors; and (3) the distinction between primary liver cancer and metastatic liver cancer. Due to the high heterogeneity of the histological type of liver cancer, existing hepatocellular protein markers are somewhat insufficient in the specificity and sensitivity of diagnosis, and often require reasonable combination, objective evaluation, and sometimes use in combination with markers of other systemic tumors.
(1) HCC: the following markers are positive for hepatocyte markers, which help to suggest tumors of hepatocyte origin, but cannot be used as a basis for distinguishing benign and malignant tumors of hepatocytes.
(1) Arginase-1: hepatocyte plasma/nucleus staining.
(2) Hepatocyte antigen: hepatocyte plasma staining.
(3) Antibodies such as CD10, polyclonal carcinoembryonic antigen and bile salt output pump protein can be specifically stained on the capillary bile duct surface of the hepatocyte membrane, which helps to confirm hepatocellular tumors.
The following markers help to distinguish benign and malignant tumors from hepatocytes.
(1) Phosphatidyl inositol protein-3: hepatocellular carcinoma cytoplasm and cell membrane staining.
(2) CD34: CD34 immunohistochemical staining does not directly label liver parenchymal cells, but can show the microvascular density of different types of liver tumors and their distribution pattern characteristics: such as hepatocellular carcinoma is diffuse, bile duct carcinoma is sparse type, hepatocellular adenoma is patchy, hepatic focal nodular hyperplasia is cord type, etc., combined with tumor histology is helpful for differential diagnosis.
(3) Heat shock protein 70: hepatocellular carcinoma cytoplasm or nucleus staining.
(4) Glutamine synthase: hepatocellular carcinoma is mostly diffuse cytoplasmic strong positive; some hepatocellular adenomas, especially β protein mutation-activated hepatocellular adenomas, can also be diffuse positive; medium intensity focal staining in HGDN, the number of positive cells < 50%; in the liver focal nodular hyperplasia is characteristic irregular map-like staining; in normal liver tissue only around the central vein staining, these characteristics help to differentiate the diagnosis.
（2）ICC
(1) Epithelial cell surface glycoprotein (MOC31): cholangiocarcinoma cell membrane staining.
(2) Cytokeratin (CK) 7/CK19: Cytoplasmic staining of cholangiocarcin cells.
(3) Muc protein-1 (muc-1): cholangiocarcinoma cell membrane staining.
Although positive for the above markers may indicate a tumor of bile duct epithelial origin, it can also be positively expressed in the non-neoplastic bile duct epithelium, and attention needs to be paid to differentiation.
（3）cHCC-CCA
HCC and ICC are two components that express the markers of their respective tumors, respectively. In addition, positive expression of markers such as CD56, CD117, and epithelial cell adhesion molecule (EpCAM) may indicate that tumors are characterized by stem cell differentiation and are more aggressive.
5. Pathological evaluation of liver cancer specimen removal after transformation/neoadjuvant therapy
(1) Specimen materials
Liver cancer excision specimens clinically labeled with preoperative transformation/neoadjuvant therapy can be treated by incising and measuring the three-dimensional dimensions at the maximum diameter of the tumor bed (the original position the tumor was in before treatment). ≤3cm small liver cancer should be taken from all materials; and tumors with >3cm should be cut at the maximum diameter by 0.5-1cm intervals, and the most representative section of tumor necrosis and residue should be selected for sampling, and attention should be paid to the tumor bed and surrounding liver tissue for mutual control, and the general specimen can also be photographed for histological observation.
(2) Microscopic evaluation
The proportion of three components of the tumor bed of liver cancer excision specimens was mainly evaluated: (1) necrotic tumor; (2) surviving tumor; (3) tumor interstitium (fibrous tissue and inflammation). The sum of these 3 areas of the tumor bed is equal to 100%. The number of materials taken should be marked in the pathology report, and the average is taken to determine the total percentage of residual tumors based on the assessment of the percentages of the above 3 components in each slice.
(3) Complete pathological response and obvious pathological response assessment
It is an important pathological indicator to evaluate the efficacy of preoperative treatment and to explore the best time for surgery.
Complete pathologic response (CPR): refers to the fact that no surviving tumor cells were found after a complete histology of a tumor bed specimen after preoperative treatment.
Significant pathologic response (MPR): Refers to the reduction of surviving tumors below the threshold that can affect clinical prognosis after preoperative treatment. MPR is often defined in lung cancer studies as a reduction in residual tumor cells in the tumor bed to ≤10% [71], which is the same as the correlation between tumor necrosis and prognosis after TACE treatment before liver cancer [72]. The specific threshold for MPR is subject to further clinical studies. It is recommended that the tumor specimens that are initially diagnosed as MPR be further expanded to clarify the scope of materials.
(4) For the histological assessment method of the degree of necrosis of liver cancer specimens after the treatment of immune checkpoint inhibitors, reference can be made to some tumor types that have carried out more relevant research [73], and the understanding of the histological characteristics of liver cancer is continuously deepened in the work, and attention is paid to observing whether there is immune-related liver damage in the peri-cancer liver tissue, including hepatocyte damage, intralobar hepatitis and cholangitis.
6. Liver cancer pathological diagnosis report
It mainly consists of a general specimen description, microscopic description, immunohistochemical examination and pathological diagnosis name, and if necessary, it can also make clinical instructions and recommendations (Appendix 4). In addition, molecular pathological examination results related to liver cancer clonal origin detection, drug target detection, biological behavior assessment, and prognosis judgment can be attached to provide clinical reference.
An overview of the main points
(1) The standardized treatment and timely delivery of liver cancer excision specimens are very important to maintain the integrity of tissues and cells and correct pathological diagnosis.
(2) Liver cancer specimens should follow the specification of "seven-point baseline material", which is conducive to obtaining information on the representative pathological biology characteristics of liver cancer.
(3) The content of the liver cancer pathology diagnosis report should be standardized and comprehensive, and special attention should be paid to the diagnosis and pathological grading assessment of MVI, an important factor affecting the prognosis of liver cancer.
Clinical diagnostic criteria and roadmap for liver cancer
Clinical diagnosis of liver cancer is performed according to the steps of the roadmap, combined with risk factors for liver cancer development, imaging features, and serological molecular markers (Figure 2).
1. Patients with HBV or HCV infection, or any cause of cirrhosis, at least once every 6 months, ultrasonography and serum AFP testing were performed to find intrahepatic nodules with a diameter of ≤2 cm, multiparameter MRI, dynamic enhancement CT, ultrasonography or hepatocyte-specific contrast medium Gd-EOB-DTPA enhancement MRI At least 2 of the 4 tests showed significant strengthening of arterial phase lesions, portal phase and/or delayed intrahepatic lesions strengthening lower than the liver parenchyma, that is, "fast in and fast out" Typical characteristics of liver cancer. A clinical diagnosis of liver cancer can be made, and for nodules with a diameter of >2 cm in the liver, as long as there is 1 typical liver cancer feature in the above four imaging tests, liver cancer can be clinically diagnosed.
2. Patients with HBV or HCV infection, or any cause of cirrhosis, follow-up found to be ≤2 cm diameter nodules in the liver, if none or only 1 of the above 4 imaging tests have typical liver cancer characteristics, liver lesion aspiration biopsy or imaging tests every 2 to 3 months and combined with serum AFP levels to confirm the diagnosis; for nodules with a diameter of > 2 cm in the liver, the above 4 imaging tests do not have typical liver cancer features, then a liver lesion puncture biopsy or every 2 to 3 is required Months of imaging follow-up combined with serum AFP levels to confirm the diagnosis.
3. Patients with HBV or HCV infection, or any cause of cirrhosis, such as elevated serum AFP, especially persistent elevation, should be subjected to imaging tests to confirm the diagnosis of liver cancer; if only 1 of the above 4 imaging tests has typical liver cancer characteristics, it can be clinically diagnosed as liver cancer; if no intrahepatic nodules are found, under the premise of excluding pregnancy, chronic or active liver disease, germ gonadal embryonic tumors and gastrointestinal tumors, Serum AFP changes should be closely followed up and an imaging review should be performed every 2 to 3 months.
concentrate
：
Typical manifestations: marked strengthening of lesions in the arterial phase (advanced stage of the main artery), decreased intensification of the portal vein and/or delayed phase, and a "fast-forward, fast-out" intensification mode. Atypical manifestations: lack of arterial phase lesion strengthening or portal vein and delayed phase intensification without decreasing or decreasing significantly, or even slightly increasing intensification.
US: Ultrasound
MRI: Multiparameter MRI
CT: CT Dynamic Enhanced Scan
CEUS: ultrasound contrast, which uses ultrasound contrast media to observe blood flow perfusion of normal and diseased tissues in real time. EOB-MRI: enhanced magnetic resonance scan of the hepatocyte-specific contrast agent disodium gadorate (Gd-EOB-DTPA).
AFP(+): Exceeds the normal value of serum AFP detection.
3 staging
The field of liver cancer treatment is characterized by multidisciplinary participation, coexistence of multiple treatment methods, common treatment methods include liver resection, liver transplantation, ablation therapy, TACE, radiation therapy, systemic anti-tumor therapy and other means, for different stages of liver cancer patients to choose a reasonable treatment method can maximize the efficacy. The choice of rational treatment requires support from high-level evidence-based medical evidence. At present, the long-term efficacy of orderly combination of standardized comprehensive therapy for the treatment of liver cancer is the best, but there is a certain contradiction between the current sub-disciplinary diagnosis and treatment system based on different treatment methods and the realization of standardized comprehensive therapy. Therefore, the diagnosis and treatment of liver cancer should pay attention to the diagnosis and treatment mode of multidisciplinary team (MDT), especially the diagnosis and treatment of difficult and complex cases, so as to avoid the limitations of single-discipline treatment, promote disciplinary communication, and improve overall efficacy. It is suggested that the MDT management of liver cancer should focus on the core indicators of the quality control of liver cancer diagnosis and treatment of the National Health Commission, but it is also necessary to consider the regional economic level and the differences in the medical capacity and conditions of various hospitals.
Surgical treatment
Surgical treatment of liver cancer is an important means for liver cancer patients to achieve long-term survival, mainly including hepatic resection and liver transplantation.
1. Basic principles of hepatic resection
(1) Thoroughness: complete removal of tumors, no residual tumors at the margins.
(2) Safety: Retain a sufficient volume and function of liver tissue (with good blood supply and good blood and bile reflux) to ensure postoperative liver function compensation, reduce surgical complications, and reduce mortality.
2. Preoperative patient's systemic condition and liver reserve function assessment
The patient's systemic condition, liver reserve function, and liver tumor status (staging and location) should be comprehensively evaluated preoperatively, and the patient's systemic status score (ECOG PS) proposed by the Eastern Cancer Association is often used to assess the patient's systemic condition, and liver reserve function is measured by hepatic function Child-Pugh score, Indocyanine green (ICG) clearance test, or transient elastography to measure liver hardness [74-79]. Findings suggest that selected patients with hepatic cancer with portal hypertension can still undergo liver resection, and long-term postoperative survival is better than other treatments [80,81]. Therefore, a more precise evaluation of the extent of portal hypertension (e.g., hepatic venous pressure gradients) [82,83] can help screen patients who are candidates for surgical resection.
If the volume of retained liver tissue is small, the remaining liver volume is measured using CT, MRI, or liver 3D reconstruction, and the remaining liver volume as a percentage of the normalized liver volume is calculated [75]. It is generally believed that liver function Child-Pugh Grade A, ICG 15min retention rate (ICG-R15) < 30% is necessary to perform surgical resection; the remaining liver volume must account for more than 40% of the standard liver volume (with chronic liver disease, liver parenchymal damage or cirrhosis) or more than 30% (without hepatic fibrosis or cirrhosis), which is also a necessary condition for surgical resection. People with liver impairment need to retain more of the remaining liver volume.
3. Indications for liver cancer resection
(1) The preferred treatment method for CNLCI.a, I.b and II.A liver cancers with good liver reserve function is surgical resection. Previous studies have shown no significant difference in efficacy between surgical resection and radiofrequency ablation for liver cancer ≤3 cm in diameter [84,85] (evidence level 1, recommendation B), but recent studies have shown that the local recurrence rate after surgical resection is significantly lower than after radiofrequency ablation [86,87], and the long-term efficacy of surgical resection is better [88-90] (evidence level 1, recommendation A). Even for recurrent liver cancer, the prognosis of surgical resection is still better than radiofrequency ablation [91] (evidence level 2, recommendation B).
(2) For patients with CNLC stage II .b liver cancer, surgical resection should not be preferred in most cases, and non-surgical treatment based on TACE is preferred. Surgical resection is likely to yield better results than other treatments, even if the number of tumors is >3, if the tumor is confined to the same segment or ipsilate hemiva, or if intraoperative ablation can be performed concurrently, surgical resection is likely to yield better results than other treatments [92,93], and surgical resection is also recommended (evidence level 2, recommendation B), but preoperative multidisciplinary evaluation is more cautious.
(3) For CNLC STAGE III.A liver cancer, surgical resection is not preferred for the vast majority of patients, and non-surgical treatment based on systemic anti-tumor therapy is the preferred choice. Surgical resection may also be considered if the following conditions are: (1) those with portal vein branch carcinoma suppositories (Cheng's classification type I/II. type) (Appendix 5), if the tumor is confined to the hemihepatic or ipsilateral hepatic, surgery may be considered for tumor removal and transportal vein embolism, followed by postoperative TACE therapy, portal vein chemotherapy, or other systemic antitumor therapy; portal vein trunk carcinoma suppositories (Cheng's classification type III.) have a higher short-term recurrence rate after surgery, and most patients have unsatisfactory postoperative survival, so it is not an absolute indication for surgical resection [94] (level of evidence). 3, recommended B). In patients with liver cancer who can be resected with portal vein carcinoma suppositories, preoperative three-dimensional conformal radiation therapy may improve postoperative survival [95] (evidence level 2, recommendation C). (2) Those who have cholangiocarcinoma suppositories but intrahepatic lesions can also be removed. (3) Some hepatic veins are violated but the lesions in the liver can be removed.
(4) For patients with hepatic portal lymph node metastasis (CNLC stage III.b), hepatic hilar lymph node dissection or postoperative external radiation therapy may be considered at the same time as removing the tumor. If the peripheral organs are violated, they can be removed together, and surgical removal may also be considered. In addition, for liver cancer found to be unsuitable for surgical resection during intraoperative exploration, intraoperative hepatic artery, portal vein intubation chemotherapy or other intraoperative local treatment measures may be considered, or non-surgical treatment such as follow-up TACE therapy and systemic antitumor therapy after recovery from surgical trauma.
4. Criteria for radical resection of liver cancer
(1) Intraoperative judgment criteria: (1) no gross eye cancer plugs are seen in the hepatic vein, portal vein, bile duct and inferior vena cava; (2) no invasion of adjacent organs, no hilar lymph nodes or distant metastases; (3) the hepatic incision margin is 1 cm ≥ the tumor boundary; if the incision margin is < 1 cm, there is no tumor cell residue on the histological examination of the liver section, that is, the incision margin is negative.
(2) Postoperative judgment criteria: (1) 1-2 months after surgery ultrasound, CT, MRI examination (two of which must be there) did not find tumor lesions; (2) such as preoperative serum AFP, DCP and other serum tumor markers are elevated, then the quantitative determination of serum tumor markers 2 months after surgery is required, and their levels are reduced to within the normal range. The rate of decline in serum tumor markers such as AFP after resection can predict the thoroughness of surgical resection early [96].
5. Surgical resection technique
Commonly used hepatic resection techniques mainly include inbound and outbound hepatic flow control techniques, hepatic dissociation techniques, and hemostasis techniques. Preoperative 3D visualization of individualized liver volume calculations and virtual hepatectomy can help design more precise resection ranges and pathways to protect the remaining liver's tubing and retain sufficient residual liver volume while achieving radical tumor resection goals [97-99] (evidence level 2, recommendation A).
In recent years, laparoscopic liver surgery has developed rapidly. Laparoscopic hepatic resection has the advantages of low trauma and rapid postoperative recovery [100], and its oncological effect is comparable to open hepatic resection in selected patients [101] (evidence level 3, recommendation C). Although the indications and contraindications of laparoscopic hepatic resection are similar in principle to open surgery, it is still recommended to conduct a comprehensive evaluation and cautious based on tumor size, tumor site, number of tumors, underlying liver disease, and the technical level of the surgical team. For patients with large liver cancer, multiple liver cancer, liver cancer located in difficult areas and in the central area immediately adjacent to important tubes, and liver cancer with severe cirrhosis, it is recommended that this treatment be carried out by an experienced physician after strict selection. Laparoscopic ultrasonography combined with indocyanine green fluorescent tumor imaging can help to detect tiny lesions and label resection ranges to obtain negative tumor margins [102].
Both anatomical resection and non-anatomical resection are commonly used hepatic resection techniques that require sufficient margins to obtain good oncology. Anatomical resection was associated with MVI with lower local recurrence rates than non-anatomical resection, although overall survival was not differentiated [103,104] (evidence level 3, recommendation B). Hepatic resection with a wide incision margin (≥1 cm) has been found to be superior to hepatic resection at narrow margins [105,106] (evidence level 1, recommendation A), particularly in patients who can preoperatively predict the presence of MVI [107].
For large liver cancers, anterior path hepatic resection of the final free perihepatic ligament may be used [108]. For multiple liver cancers, surgical resection combined with intraoperative ablation may be used [109] (evidence level 4, recommendation C). In patients with portal vein cancer suppositories, portal vein ebolectomy should be performed to temporarily block blood flow to the healthy portal vein to prevent the spread of cancer embolus [110]. For patients with hepatic venous carcinoma suppositories or vena cava cancer suppositories, a complete hepatic flow blockade may be performed to remove the cancer embolus as much as possible [111]. In patients with hepatic cancer with cholangiocarcinoma suppository, removal of liver tumors is accompanied by bile duct resection to obtain the opportunity for radical resection [80,112,113] (evidence level 3, recommendation C).
For liver cancer with severe cirrhosis, deep tumor location, and multiple nodules found on post-abdominal exploration, intraoperative ablation therapy may be considered to reduce the risk of surgery.
6. Comprehensive treatment strategy based on surgery
Based on data from previous large cases, overall survival after surgery for advanced liver cancer (CNLC STAGE II.b, III.a, III.b) is not satisfactory, but surgical resection can still benefit some patients in the absence of other effective treatments [80] (evidence level 4, recommendation C). The effects of systematic antineoplastic therapy and/or topical therapy to control tumors can provide more possibilities for radical resection, reduced postoperative recurrence, and improved prognosis in patients with advanced liver cancer [114] (evidence level 4, recommendation B). Therefore, the strategy of direct surgical resection in patients with intermediate and advanced liver cancer needs to be re-understood. Exploring new surgically-based comprehensive treatment strategies for mid- and advanced liver cancer has become a recent focus.
(1) Potentially resectable translational therapy of liver cancer
Conversion therapy, which converts unresectable liver cancer into resectable liver cancer, is one of the pathways for radical resection and long-term survival in patients with advanced liver cancer [115]. For potentially resectable liver cancer, multimodal, high-intensity antineoplastic therapy strategies are recommended to promote its transformation [114,116-119], while balancing the safety and quality of life of treatment [115].
(1) Translational therapy for tumors
(1) Systemic antineoplastic therapy: single or combined application of systemic antineoplastic therapy is one of the main methods of translational therapy for advanced liver cancer [114] (evidence level 4, recommendation B). The depth, speed and duration of liver cancer remission, as well as organ-specific remission, are important factors influencing subsequent treatment decisions. The effects of different drug combinations on liver tissue and the safety of subsequent surgeries need to be explored more.
(2) Topical treatments: local treatments including TACE [120] (evidence level 3, recommendation B), hepatic arterial infusion chemotherapy (HAIC)[121] (evidence level 4, recommended C) and other local treatments create potential surgical resection opportunities for patients with initially unresectable liver cancer, and can translate into survival benefits. Radiation therapy combined with HAIC [122] and HAIC with TACE [123] can further improve conversion. Systemic antineoplastic therapy combined with topical therapy is expected to achieve higher tumor remission and higher conversion resection rates [124] (Evidence Grade 4, Recommendation B)
(2) Conversion therapy for insufficient residual liver volume:
(1) Trans-portal vein embolization (PVE) tumor is located in the hemihepatic, so that the remaining liver compensatory hyperplasia and then resection of the tumor [125]. The success rate of PVE is 60% to 80%, and the complication rate is about 10% to 20%. Residual hepatic hyperplasia after PVE is relatively long (usually 4 to 6 weeks), and more than 20% of patients lose the opportunity to operate due to tumor progression or insufficient residual hepatic hyperplasia (evidence level 3, recommendation B).
(2) Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is suitable for patients with expected remaining liver volume accounting for less than 30% to 40% of standard liver volume. In recent years, a variety of improved ALPPS procedures have emerged, focusing on the first stage of surgery hepatic cross-sectional separation (partial separation and separation using radiofrequency ablation, microwave, tourniquet, etc.) and the use of laparoscopic minimally invasive alpps [126,127]. Preoperative evaluation is important and requires a combination of consideration of the degree of cirrhosis, the age of the patient, and the ability to withstand two short-term surgeries [128]. ALPPS can improve the resection rate of liver cancer in the short term, and the ability to rapidly induce residual liver hyperplasia is better than PVE [129] (evidence level 2, recommendation A), and the risk of tumor progression is minimized due to the short interval between two stages of surgery, and the tumor resection rate is 95% to 100%. The results of the study showed that ALPPS was better than TACE [130] in treating large or multiple liver cancers (evidence level 3, recommendation B). It is necessary to pay attention to the trauma of two surgeries in the short term and the possibility of failure of the second stage of surgery, and it is recommended to carefully and reasonably select the surgical object and perform ALPPS by an experienced surgeon. In addition, ALPPS surgery should be performed with caution in elderly patients with liver cancer.
(2) Neoadjuvant therapy
According to the definition of the National Institute of Cancer, neoadjuvant therapy is the treatment of shrinking the tumor before the main treatment (usually surgery), and common neoadjuvant therapy includes systemic anti-tumor therapy, interventional therapy, radiation therapy, etc., the goal of which is to reduce postoperative recurrence and prolong postoperative survival. For resectable intermediate and advanced liver cancer (CNLC II.b, III.a), neoadjuvant therapy converts liver cancer with poor oncological characteristics into liver cancer with better oncology characteristics, thereby reducing postoperative recurrence and prolonging survival. If liver cancer with portal vein cancer suppositories can be surgically removed, preoperative three-dimensional conformal radiation therapy may improve efficacy [95] (level of evidence 2, recommendation C).
However, for surgically resectable liver cancer, preoperative TACE does not prolong survival [131,132] (evidence level 2, recommendation A). Strategies such as immunotherapy in combination with targeted agents, immunotherapy monotherapy, or combination therapy are used in preoperative or perioperative therapy where liver cancer can be surgically removed and are expected to further improve surgical efficacy [133] (evidence level 2, recommendation B). For earlier liver cancer (CNLC I.a, I.b, II.A), clinical studies still need to be confirmed by clinical studies to confirm whether preoperative treatment can improve patient survival and reduce recurrence.
(3) Adjuvant therapy
The rate of tumor recurrence and metastasis in the 5 years after liver cancer resection is as high as 40% to 70%, which is related to the presence of microdispersible foci or multicentre before surgery, so all patients need to be closely followed up after surgery. In patients at high risk of recurrence, two randomized controlled studies confirmed that postoperative TACE therapy had the effect of reducing recurrence and prolonging survival [134,135] (evidence level 1, recommendation A). Another randomized controlled study showed that treatment with locust ear granules after hepatic resection reduced recurrence and prolonged survival [136] (evidence level 2, recommendation A). In HBV-infected patients with liver cancer, nucleoside analogue antiviral therapy not only controls underlying liver disease, but also helps to reduce postoperative tumor recurrence rates [137-139] (evidence level 1, recommendation A).
Direct-acting antiviral agents (DAAs) can provide a sustained virological response in patients with HCV-infected liver cancer, and there are no conclusive data to suggest that TREATMENT of DAAs is associated with an increased or decreased risk of tumor recurrence after liver cancer surgery, a difference in the timing of recurrence, or the aggressiveness of recurrent liver cancer [140] (evidence level 3, recommendation C). In addition, postoperative translarial catheterization chemotherapy combined with TACE in patients with portal vein cancer suppository may also prolong patient survival [141] (evidence level 2, recommendation A).
Although clinically randomized studies suggest that α-interferon can reduce recurrence and prolong survival [142-144] (evidence level 1, recommendation B), it remains controversial [145]. MiR-26a expression in liver cancer has been reported to be associated with the efficacy of α-interferon therapy [146], and this result is subject to further multicenter randomized controlled trials. Strategies for postoperative immunotherapy, targeted drugs, and HAICs alone or in combination are being actively explored [147]. Once a tumor recurrence is found, according to the characteristics of the recurrent tumor, re-surgical resection, ablation therapy, interventional therapy, radiation therapy or systemic anti-tumor therapy can be selected to prolong the survival of the patient
(1) Hepatic resection is an important means for liver cancer patients to obtain long-term survival.
(2) The principle of hepatic resection is to completely remove the tumor and retain sufficient volume and functional liver tissue, so it is very important to improve the preoperative liver reserve function assessment and oncological assessment.
(3) It is generally considered that liver function Child-Pugh Grade A, ICG-R15<30% is necessary for the implementation of surgical resection; the remaining liver volume must account for more than 40% of the standard liver volume (with chronic liver disease, liver parenchymal damage or cirrhosis) or more than 30% (without liver fibrosis or cirrhosis), which is also a necessary condition for surgical resection. People with liver impairment need to retain more of the remaining liver volume. Preoperative evaluation also includes the determination of liver hardness and portal hypertension.
(4) The preferred treatment for CNLC stage I.a, stage I.b, and stage II.a liver cancer with good liver reserve function is surgical resection. Surgical resection is not appropriate in patients with CNLC stage II.b and stage III.a liver cancer, but some patients still have the opportunity to benefit from surgical resection after careful preoperative multidisciplinary evaluation.
(5) Hepatic resection often uses blood flow control techniques into the liver (hepatic artery and portal vein) and out of the liver (hepatic vein); preoperative three-dimensional visualization technology helps to improve the accuracy of liver resection; laparoscopic technique helps to reduce surgical trauma, but for large liver cancer, multiple liver cancer, liver cancer located in difficult areas and central areas adjacent to important canals, liver cancer and liver cancer complicated by severe cirrhosis, it is recommended to be implemented by experienced physicians after strict selection.
(6) For potentially resectable liver cancer, it is recommended to adopt multi-mode, high-intensity treatment strategies to promote its transformation. For patients with smaller remaining liver volumes, ALPPS or PVE can be used to improve resection rates by compensating hyperplasia of the remaining liver.
(7) Postoperative adjuvant therapy for liver cancer takes reducing recurrence as the main goal. TACE treatment in patients at high risk of postoperative recurrence can reduce recurrence and prolong survival, and postoperative oral administration of locust ear granules can also help reduce recurrence and prolong survival. In addition, postoperative use of nucleoside analogues anti-HBV therapy and α-interferons also have the effect of inhibiting recurrence and prolonging survival.
(8) The application strategy of systemic anti-tumor therapy and local treatment alone or in combination in the perioperative period is being actively explored.
7. Liver transplantation
(1) Indications for liver cancer liver transplantation
Liver transplantation is one of the radical treatment methods for liver cancer, especially for patients with small liver cancer who are decompensated and unsuitable for surgical resection and ablation. Appropriate indications for liver cancer liver transplantation are key to improving the efficacy of liver cancer liver transplantation, ensuring that valuable donor liver resources are used fairly and appropriately, and balancing differences in prognosis in patients with or without tumors [148] (evidence level 3, recommendation A).
Regarding the indications for liver cancer liver transplantation, the Milan standard and the University of California, San Francisco (UCSF) standard are mainly used internationally. There is no unified standard in China, and many units and scholars have successively proposed different standards, including the Shanghai Fudan Standard [149], the Hangzhou Standard [150], the West China Standard [151] and the Sanya Consensus [152], which are consistent for the absence of large blood vessel invasion, lymph node metastasis and extrahepatic metastasis, but the requirements for tumor size and number are not the same. The above domestic standards, without significantly reducing the overall survival rate after surgery, have expanded the scope of application of liver cancer liver transplantation to varying degrees, so that more liver cancer patients can benefit from liver transplantation, but multi-center collaborative research is needed to support and prove, so as to obtain high-level evidence-based medical evidence. After full discussion by the expert group, this guideline recommends the use of the UCSF standard at this stage, that is, the diameter of a single tumor ≤ 6.5 cm; the number of tumors is ≤ 3, of which the maximum tumor diameter is ≤ 4.5 cm, and the total tumor diameter is ≤ 8.0 cm; no large blood vessel invasion. The Basic Principles and Core Policies for Organ Allocation and Sharing in Chinese have specific instructions for liver cancer liver transplantation, stipulating that liver cancer recipients can apply for a special case score for early-stage hepatocellular carcinoma, and successful applications can obtain a model for end-stage liver disease (MELD) score of 22 points (≥ 12-year-old liver transplant waiters) and renew the special case score every 3 months.
Patients with liver cancer who meet the indications for liver cancer transplantation can undergo bridging therapy to control tumor progression while waiting for donor liver to prevent patients from losing the opportunity for liver transplantation, and there is currently limited evidence on whether to reduce the probability of recurrence after liver transplantation [153,154] (evidence level 2, recommendation C). Some patients with liver cancer whose tumor burden exceeds the indication criteria for liver transplantation can be reduced by reducing the tumor burden with reduced-stage therapy to meet the indications. Palliative care commonly used to treat liver cancer can be used for bridging or descending therapy, including TACE, yttrium-90 radiation embolism, ablation therapy, stereotactic body radiation therapy (SBRT), and systemic antitumor therapy. In cases of liver cancer after successful hypotherapy, the prognosis after liver transplantation was better than in non-liver transplant cases [155,156] (evidence level 2, recommendation B).
Advances in surgical techniques have expanded the range of available donor livers. The indications for the treatment of liver cancer by living donor liver transplantation can be attempted to expand further [157,158] (evidence level 4, Recommendation C).
(2) Prevention and treatment of recurrence of liver cancer after liver transplantation
Tumor recurrence is a major problem after liver transplantation in liver cancer [159]. Risk factors include tumor staging, tumor vascular invasion, preoperative serum AFP levels, and immunosuppressant regimens. Early postoperative withdrawal or hormone-free regimens [160] and reducing the amount of calcineurin inhibitors early after liver transplantation can reduce tumor recurrence rates [161] (evidence level 2, recommendation A). Immunosuppression regimens based on mammalian target of rapamycin (mTOR) inhibitors (e.g., rapamycin, everolimus) after liver transplantation can reduce tumor recurrence and improve survival [162-166] (evidence level 1, recommendation A).
Once the tumor relapses and metastasizes after liver cancer transplantation (75 percent of cases occur within two years of liver transplantation), the disease progresses rapidly, and the median survival time for patients with relapsed metastasis is 7 to 16 months [167]. On the basis of multidisciplinary diagnosis and treatment, a combination of treatment including changing the immunosuppressive regimen, resurgesion, TACE, ablation therapy, radiation therapy, and systemic antitumor therapy may prolong patient survival [168,169] (evidence level 3, recommendation B). Immune checkpoint inhibitors should be used with caution in the preoperative and postoperative treatment of liver cancer liver transplantation [170,171] (evidence level 4, recommendation C).
(1) Liver transplantation is one of the radical treatment methods for liver cancer, especially for patients with small liver cancer who are decompensated and not suitable for surgical resection and ablation treatment.
(2) Recommend the UCSF standard as the indication standard for liver transplantation in Chinese liver cancer.
(3) Early withdrawal/hormone-free regimen after liver cancer liver transplantation, reducing the amount of calcineurin inhibitors in the early post-transplantation period, and using immunosuppressive regimens based on mTOR inhibitors (such as rapamycin and everolimus) can help reduce tumor recurrence and improve survival.
(4) Once the tumor recurs and metastasizes after liver cancer liver transplantation, the disease progresses rapidly, and comprehensive treatment on the basis of multidisciplinary diagnosis and treatment may prolong the survival time of patients.
Ablation therapy
Although surgery is considered the preferred treatment for radical treatment of liver cancer, some patients cannot tolerate surgery because most patients have varying degrees of cirrhosis. At present, ablation therapy, which has been widely used, has the characteristics of less impact on liver function, less trauma and exact efficacy, and can obtain similar efficacy to surgical resection in some patients with early liver cancer.
Liver cancer ablation treatment is a type of treatment method that directly kills tumor tissue by means of medical imaging technology, targeting and locating tumor lesions, and directly killing tumor tissues locally. It mainly includes Radiofrequency ablation (RFA), Microwave ablation (MWA), Percutaneous ethanol injection (PEI), Cryoablation (CRA), and High intensity focused ablation ultrasound ablation(HIFU), laser ablation (LA), Irreversible electroporation (IRE), etc. Commonly used guided modalities of ablation therapy include ultrasound, CT, and MRI, the most common of which is ultrasound guidance, which is convenient, real-time, and efficient. CT and MRI can be used to observe and guide lesions that are not accessible with conventional ultrasound. CT and MRI guidance techniques can also be applied to the ablation treatment of liver cancer metastases such as lung, adrenal glands, and bone.
There are four paths of ablation: percutaneous, laparoscopic, open or transenoscopic. Most small liver cancers can be ablated by percutaneous puncture, which has the advantages of economy, convenience and minimally invasive. Liver cancer located under the hepatic envelope, especially liver cancer protruding outside the hepatic capsular, has a greater risk of percutaneous puncture ablation, and liver cancer (close to the heart, diaphragm, gastrointestinal tract, gallbladder, etc.) with difficult imaging guidance may be considered to use the method of transaroscopic ablation, open abdominal ablation or water isolation techniques.
Ablation therapy is primarily indicated for CNLC stage I.a and some stage I.b liver cancers (i.e., single tumors, ≤5 cm in diameter; or 2 to 3 tumors, maximum diameter ≤3 cm); no vascular, bile duct, and adjacent organ invasion, and distant metastases, and liver function Child-Pugh A/B grade, and can achieve radical therapeutic effects [84,89,172-175] (evidence level 1, recommendation A). Single or multiple tumours with a diameter of 3 to 7 cm that are not suitable for surgical resection can be treated in combination with TACE, which is more effective than ablation alone [176-179] (evidence level 1, recommendation B).
1. At present, ablation treatment methods are commonly used
(1) RFA: RFA is a common ablation method for minimally invasive treatment of liver cancer, and its advantages are convenient operation, short hospitalization time, accurate efficacy, and good controllability of ablation range, especially suitable for patients with advanced age, other diseases, severe cirrhosis, tumors located in deep liver or central liver cancer. For patients with surgery-friendly early-stage liver cancer, RFA has similar or slightly lower tumor-free survival and overall survival than surgical resection, but has low complication rates and short hospital stays [84,85,89,172-175] (evidence level 1, recommendation A). For a single liver cancer ≤2 cm in diameter, there is evidence that RFA is similar to surgical resection, particularly in centrally located liver cancer [180,181] (evidence grade 3, recommendation A). The technical requirements for RFA treatment are overall tumor inactivation and adequate ablation safety boundaries, and minimize normal liver tissue damage, premised on an accurate assessment of the extent of tumor invasion and identification of satellite foci. Therefore, emphasis is placed on precise imaging before treatment. Ultrasound contrast technology helps to confirm the actual size and morphology of the tumor, define the scope of tumor invasion, detect micro-liver cancer and satellite lesions, especially in the process of ultrasound-guided ablation can provide a reliable reference for formulating ablation program to inactivate tumors.
(2) MWA: MWA has been widely used in recent years, and there is no statistical difference with RFA in terms of local efficacy, complication rate, and long-term survival [182-184] (evidence level 1, recommendation B). It is characterized by high ablation efficiency, short ablation time required, and reduced "heat sinking effect" in RFA. The use of temperature monitoring systems helps to regulate parameters such as power, determine the effective thermal field range, protect the surrounding tissue of the thermal field from thermal damage, and improve the safety of MWA ablation. As for the choice of MWA and RFA ablation methods, a more suitable ablation method can be selected according to the size and location of the tumor [185].
(3) PEI: PEI has a definite effect on liver cancer ablation ≤2 cm in diameter, and the long-term effect is similar to RFA, but the local recurrence rate of >2 cm tumor is higher than that of RFA [186] (evidence level 2, recommendation B). Pei has the advantage of being safe and is particularly suitable for high-risk areas such as the hepatic hilar, gallbladder and gastrointestinal tissues of cancer foci, but multiple, multi-point punctures are required to achieve intratumor diffusion of the drug.
2. Basic technical requirements
(1) The operator must go through strict training and accumulate sufficient practical experience to master the advantages and disadvantages of various ablation techniques and the indications for treatment selection. Before treatment, the patient's systemic condition, liver function status, coagulation function and tumor size, location, number and relationship with neighboring organs should be fully assessed, and a reasonable puncture path, ablation plan and postoperative care should be formulated to achieve an effective ablation safety range under the premise of ensuring safety.
(2) According to the size and location of the tumor, emphasize the selection of suitable image guidance equipment (ultrasound or CT, etc.) and ablation method (RFA, MWA or PEI, etc.), and multi-modal fusion image guidance can be used if conditions permit.
(3) Liver cancer adjacent to the hepatic portal or near the primary and secondary bile ducts requires caution to apply ablation therapy to avoid complications such as damage to the bile ducts. The PEI method is safer, or the ablation combined PEI method. If thermal ablation is used, there should be sufficient safe distance between the tumor and the primary and secondary liver tubes (at least more than 5 mm) and safe ablation parameters (low power, short time, intermittent radiation) should be used. Temperature monitoring methods are recommended for conditional ablation equipment. Combination therapy with TACE plus ablation is recommended for lesions >5 cm in diameter, which is superior to ablation alone.
(4) The ablation range should strive to cover at least 5mm of paracous tissue to obtain a "safe edge" and completely kill the tumor. For cancer lesions with unclear boundaries and irregular shapes, it is recommended to expand the scope of ablation appropriately when the adjacent liver tissue and structural conditions permit.
3. For liver cancer treatment options with a diameter of 3 to 5 cm
Several prospective randomized controlled trials and systematic retrospective analyses have shown that surgical resection is the preferred choice [90,172,174] (evidence level 1, recommendation A). In clinical practice, the patient's general condition and liver function, the size, number and location of the tumor should be determined, and combined with the technology and experience of physicians engaged in ablation therapy, the appropriate initial treatment should be selected after comprehensive consideration. It is generally assumed that surgical resection should be preferred if the patient is able to tolerate hepatic resection, as well as if the liver cancer is superficial or at the edge of the liver or at high risk of liver cancer that is not suitable for ablation. For liver cancers with 2 to 3 foci located in different areas, or in deep or central livers, ablation therapy or surgical resection in combination with ablation can be chosen.
4. Evaluation and follow-up after ablation treatment of liver cancer
The recommended regimen for assessing local efficacy is to review dynamic-enhanced CT, multiparametric MRI scan, or ultrasound approximately 1 month after ablation to evaluate the effects of ablation. In addition, serologic tumor marker dynamics should be detected. Imaging evaluation of ablation effect can be divided into [187] :(1) complete ablation: after dynamic enhancement CT, multiparameter MRI scan or ultrasound follow-up, the arterial phase of tumor ablation lesion is not strengthened, indicating complete tumor necrosis; (2) incomplete ablation: after dynamic enhancement CT, multi-parameter MRI scan or ultrasound follow-up, there is local strengthening in the arterial phase of the tumor ablation lesion, indicating tumor residue. If there is tumor residue after treatment, re-ablation therapy can be performed, and if there is still tumor residue after 2 ablations, ablation therapy should be abandoned and other therapies should be used. Serological tumor markers, ultrasound imaging, enhanced CT, or multiparametric MRI scans should be followed up regularly after complete ablation, usually every 2-3 months, in order to timely identify possible local recurrences and new intrahepatic foci, and to effectively control tumor progression by taking advantage of the advantages of minimally invasive ablation therapy and ease of easy and easy to repeat.
5. Combination of liver cancer ablation and systemic anti-tumor therapy
Ablation combined system therapy is still in the clinical exploration stage. Ablation therapy has been shown to enhance the release of tumor-associated antigens and neoantigens, enhance the specific T cell response of antigens associated with liver cancer, and activate or enhance the body's immune response to tumors [188-190]. Ablation therapy combined with immunotherapy can produce synergistic antitumor effects [188,191,192]. A number of relevant clinical studies are currently underway.
(1) Ablation therapy is suitable for CNLC stage I.a and some stage I.b liver cancer (that is, a single tumor, ≤5 cm in diameter; or 2 to 3 tumors, the maximum diameter ≤3 cm), which can obtain a radical therapeutic effect. Single or multiple tumours with a diameter of 3 to 7 cm that cannot be surgically removed can be treated in combination with TACE.
(2) For liver cancer patients with a diameter of £3 cm, the tumor-free survival rate and overall survival rate of ablation therapy are similar or slightly lower than that of surgical resection, but the complication rate and length of hospital stay are lower than that of surgical resection. For a single liver cancer ≤2 cm in diameter, ablation therapy is similar to surgical resection, particularly central liver cancer.
(3) There is no significant difference between RFA and MWA in terms of local efficacy, complication rate and long-term survival, and can be selected according to the size and location of the tumor.
(4) The long-term efficacy of PEI on liver cancer with a diameter of ≤2 cm is similar to that of RFA. Pei has the advantage of being safe, especially suitable for cancer lesions close to high-risk areas such as the hepatic hilar, gallbladder and gastrointestinal tissue, but multiple, multi-point punctures are required to achieve intratumor diffusion of the drug.
(5) Dynamic enhancement CT, multiparameter MRI scan, ultrasound and serological tumor markers are regularly reviewed after ablation therapy to evaluate the ablation effect.
Transarterial chemoembolization
TACE is a commonly used non-surgical treatment for liver cancer [193-198]
1. Basic principles of TACE
(1) It is required to be performed under a digital subtraction angiograph;
(2) Must strictly grasp the indications for treatment;
(3) It must be emphasized that hyper-selective intubation to the tumor is used to provide for endovascular therapy;
(4) It must be emphasized to protect the liver function of patients;
(5) Emphasis must be placed on the standardization and individualization of treatment;
(6) If the tumor continues to progress after 3 to 4 TACE treatments, it should be considered to switch to or combine other treatment methods, such as ablation therapy, systemic anti-tumor therapy, radiation therapy and surgery.
2. Indications for TACE
(1) CNLC I.a, I.b and II.a liver cancer patients who have indications for surgical resection or ablation therapy, but are unable or unwilling to accept the above treatment methods due to non-surgical reasons such as advanced age, insufficient liver function reserve, and high-risk tumor sites;
(2) IN PATIENTS WITH CNLC ii.b, III.a and some stage III .b liver cancer, liver function Child-Pugh A/B grade, ECOG PS score 0~2;
(3) Liver cancer patients whose portal vein trunk is not completely blocked, or who are completely blocked but have rich portal compensatory collateral vessels or who can restore portal vein blood flow through portal vein stent implantation;
(4) Liver cancer patients with hepatic artery-portal vein static shunt causing portal hypertension bleeding;
(5) Patients with high-risk recurrence factors (including multiple tumors, combined gross or microscopic cancer embolus, palliative surgery, postoperative AFP and other tumor markers have not fallen to the normal range, etc.) Liver cancer patients can be treated with auxiliary TACE to reduce recurrence and prolong survival;
(6) TACE treatment before the initial unresectable liver cancer surgery can achieve transformation and create opportunities for surgical resection and ablation;
(7) Bypass therapy during the waiting period of liver transplantation;
(8) Patients with spontaneous rupture of liver cancer.
3. TACE contraindications
(1) Severe liver dysfunction (Child-Pugh C grade), including jaundice, hepatic encephalopathy, refractory ascites or hepatorenal syndrome;
(2) Coagulation dysfunction that cannot be corrected;
(3) The portal vein trunk is completely blocked by cancer thrombosis/thromboembolism, and there is little collateral vascular formation;
(4) Those who are seriously infected or co-infected with active hepatitis and cannot be treated at the same time;
(5) Extensive distant metastasis of the tumor, estimated survival < 3 months;
(6) Cachexia or multi-organ failure;
(7) The proportion of tumors in the total liver volume ≥ 70% (if the liver function is basically normal, a small amount of iodine oil emulsion and granular embolism can be considered for phased embolism);
(8) Peripheral blood leukocytes and platelets are significantly reduced, the < of white blood cells is 3.0×109/L, and the platelet < 50× 109/L (non-absolute contraindications, such as hypersplenism, excluding chemotherapy bone marrow suppression);
(9) Renal dysfunction: serum creatinine > 2mg/dl or serum creatinine clearance < 30ml/min.
4. TACE operating procedures points and classification[199,200]
(1) Standardized arteriography: usually using the Seldinger method, percutaneous puncture of the femoral artery (or radial artery) route intubation, the catheter is placed in the trunk of the abdominal cavity or the common hepatic artery for DSA, subtraction image acquisition should include the arterial stage, parenchymal phase and static pulse phase; if it is found that some parts of the liver are sparse/deficient or the tumor is incompletely stained, it is necessary to find the lateral branch artery of the tumor for blood supply, and the angiography of the superior mesenteric artery, left gastrointestinal artery, subphragm artery, right renal artery (right adrenal artery) or intrathoracic artery and other angiography. To find the hepatic artery of ectopic origin or lateral branch of the lateral branch of the lateral hepatic artery to feed the blood vessels. Carefully analyze the contrast manifestations to determine the tumor location, size, number, and blood supply artery branches.
(2) According to the different arterial intubation chemotherapy and embolization operations, it is usually divided into:
(1) Arterial perfusion chemotherapy or HAIC (see Appendix 6 for specific applications): refers to the perfusion chemotherapy of the arterial supply of blood through tumors, including indwelling catheters for continuous perfusion chemotherapy, commonly used chemotherapy drugs such as anthracycline, platinum and fluorouracil, etc., and the concentration and time of perfusion drugs need to be designed according to the pharmacokinetic characteristics of chemotherapy drugs [201]. (2) Transarterial embolization (TAE): simply using granular embolism to embolize the blood-supplying artery branch of the tumor.
(3) TACE: refers to the emulsion of iodized oil with chemotherapy drugs or drug-carrying microspheres, supplemental embolic agents [gelatin sponge particles, blank microspheres, polyvinyl alcohol particles (Polyvinyl alcohol, PVA)] and other embolization treatment of the arterial branch of the tumor supply. All of the donor blood vessels of the tumor should be embolized as much as possible during embolization to desangibility of the tumor as much as possible. According to the different embolic agents, it can be divided into conventional TACE (Conventional-TACE, cTACE) and drug-eluting beads TACE (Drug-eluting beads-TACE, DEB-TACE; also known as drug-carrying microspheres TACE).
cTACE refers to embolization therapy with iodized oil chemotherapy drug emulsions as the mainstay, supplemented by gelatin sponge particles, blank microspheres or PVA. Usually a part of the chemotherapy drug is perfused first, and the general perfusion time should not be < 20min. Another part of the chemotherapy drug is then mixed with iodized oil into an emulsion for embolization. Super liquefied iodized oil and chemotherapy drugs need to be fully mixed into emulsions, and the dosage of iodized oil is generally 5 to 20 ml, and the maximum is not more than 30 ml. Under fluoroscopic surveillance, the endpoint of iodized oil embolism is visualized according to whether the iodide oil deposition in the tumor area is dense and whether small branches of the portal vein have appeared in the perigma area. After embolization of iodized oil emulsion, a granular embolic agent is added. Try to avoid embolic reflux embolizing normal liver tissue or entering non-target organs. DEB-TACE refers to the use of drug-eluting microspheres loaded with chemotherapeutic drugs as the main embolic therapy.
Drug-carrying microspheres can be loaded with doxorubicin, irinotecan and other positively charged chemotherapy drugs, the size of the drug-loaded microspheres is mainly 70-150μm, 100-300μm, 300-500μm or 500-700μm, etc., should be based on the tumor size, blood supply and therapeutic purposes of the choice of different particle size of the microspheres, often used 100-300μm, 300-500μm. DEB-TACE can embolize the blood supply arteries of liver cancer to make tumor ischemia necrosis, and at the same time, as a carrier of chemotherapy drugs, the advantage of continuous and stable release of drugs can make the tumor locally reach a higher blood drug concentration. DeB-TACE bolus speed is recommended at 1 ml/min, and attention should be paid to microsphere embolization and redistribution, embolization of the distal tumor to nourish the artery as fully as possible, while care should be taken to preserve the proximal blood supply branch of the tumor and reduce the damage of microsphere reflux to normal liver tissue [202].
(3) Fine TACE treatment: In order to reduce the heterogeneity of tumors leading to differences in TACE efficacy, fine TACE treatment is advocated. Fine TACE includes:
(1) Microcatheter superselect intubation into the blood supply artery branch of the tumor for embolization [199,202,203];
(2) Recommend the use of cone beam CT technique as an aid in TACE surgery for accurate intubation of target vessels and monitor the efficacy after embolization [204];
(3) Rational application of embolic materials, including iodized oils, microspheres, drug-eluting microspheres, etc. [205];
(4) Different embolic endpoints are used according to the patient's tumor status, liver function and treatment purpose.
5. Common adverse reactions and complications after TACE surgery
The most common adverse effect of TACE treatment is postembolic syndrome, which is characterized by fever, pain, nausea, and vomiting. The cause of fever and pain is local tissue ischemia and necrosis after the hepatic artery is embolized, while nausea and vomiting are mainly related to chemotherapy drugs. In addition, there are other common adverse reactions such as puncture bleeding, decreased white blood cells, transient liver dysfunction, renal impairment, and dysuria. Adverse effects after interventional therapy last for 5 to 7 days, and most patients recover completely after symptomatic treatment.
Complications: acute liver and kidney function impairment; gastrointestinal bleeding; cholecystitis and gallbladder perforation; liver abscess and bile tumor formation; embolic ectopic embolism (including iodized oil lung and brain embolism, gastrointestinal perforation, spinal cord injury, diaphragm injury, etc.).
6. Efficacy evaluation of TACE
According to mRECIST and EASL evaluation criteria, the local efficacy of liver cancer was evaluated, and the long-term efficacy index was overall survival (OS), and the short-term efficacy was objective response rate (ORR), TACE treatment to disease progression time.
7. The main factors affecting the long-term efficacy of TACE[193]
(1) The degree of cirrhosis and liver function status;
(2) Serum AFP level;
(3) Tumor burden and clinical stage;
(4) Whether the tumor envelope is complete;
(5) Whether there is a cancer plug in the portal vein/hepatic vein and inferior vena cava;
(6) Tumor blood supply;
(7) Pathological typing of tumors;
(8) The patient's physical fitness status;
(9) Serum HBV-DNA level in patients with a background of chronic hepatitis B;
(10) Whether combined with ablation, molecular targeted therapy, immunotherapy, radiation therapy and surgery and other comprehensive treatment.
8. Follow-up and treatment between TACE
It is generally recommended to follow up on CT and/or multiparameter MRI scans, tumor-related markers, liver and kidney function, and blood routines at 4 to 6 weeks after the first TACE treatment; if imaging follow-up shows that iodine oil deposition in liver tumor foci is dense, tumor tissue necrosis is not strengthened, and there is no new lesion, TACE therapy can be not done for the time being. The need for TACE therapy and frequency should be determined by the results of follow-up, mainly including changes in the patient's response to the previous treatment, liver function, and physical condition. Follow-up can be done at intervals of 1 to 3 months or more to evaluate liver tumor survival based on CT and/or MRI dynamic enhancement scans to determine whether TACE treatment is needed again. TACE treatment is often 3 to 4 or more for large liver cancer/massive liver cancer. TACE is currently advocated in combination with other treatments with the aim of controlling tumors, improving patient quality of life and prolonging survival.
9. TACE treatment points of attention
(1) Advocate fine TACE treatment: mainly for the microcatheter super-selective intubation to the blood supply artery branch of the tumor, accurately inject iodized oil emulsion and granular embolic agents to improve efficacy and protect liver function.
(2) There was no significant difference in the overall efficacy of DEB-TACE and cTACE therapy, but DEB-TACE had some advantages in terms of objective efficacy of tumors [205] (evidence level 1, recommendation B).
(3) Attach importance to local treatment combined with local treatment, local treatment combined with system anti-tumor therapy [193]:
(1) TACE combined ablation therapy: In order to improve the efficacy of TACE, it is advocated to combine ablation therapy as appropriate on the basis of TACE therapy, including RFA, MWA, and freezing [206, 207 (] Evidence level 3, recommendation B). There are currently two clinical treatments of TACE combined with thermal ablation: sequential ablation: TACE treatment first, plus ablation therapy within 1 to 4 weeks after surgery, and simultaneous ablation: ablation therapy given at the same time as TACE treatment can significantly improve clinical efficacy and reduce liver function damage [206].
(2) TACE combined with external beam radiation therapy [208,209] (evidence level 1, recommendation B): mainly refers to the treatment of portal vein main trunk carcinoma suppositories, inferior vena cava cancer suppositories, and localized large liver cancer after interventional therapy.
(3) TACE combined with secondary surgical resection: Surgical resection is recommended when large liver cancer or massive liver cancer is transformed after TACE therapy and the opportunity for secondary surgery is obtained [120,123] (evidence level 3, recommendation A).
(4) TACE combined with other anti-tumor therapies: including combined molecular targeted drugs, immunotherapy, systemic anti-tumor therapy, radioimmunity and targeted drugs.
(5) TACE combined with antiviral therapy: TACE treatment in patients with HBV and HCV background liver cancer should be treated with aggressive antiviral therapy [210,211] (evidence level 3, recommendation A).
(4) For patients with liver cancer with portal vein cancer suppositories, on the basis of TACE, portal vein stenting combined with iodine-125 particle strips or iodine-125 particle portal vein stenting can be used to effectively treat portal vein trunk carcinoma suppositories [212(] Evidence level 2, recommendation B). Iodine-125 particles are used or direct puncture implantation of iodo-125 particles for the treatment of portal vein primary branch carcinoma suppositories [213,214] (evidence level 4, recommended C).
(5) Prophylactic TACE therapy in patients with high-risk recurrence after surgery [134,135] (evidence level 1, recommendation A): For patients with multiple tumors, combined with gross or microscopic cancer embolus, and tumor diameter >5 cm, prophylactic TACE can prolong the overall survival and tumor-free survival of patients.
(1) TACE is a commonly used non-surgical treatment method for liver cancer, which is mainly suitable for patients with CNLC II.b, III.a and some STAGE III .b liver cancer.
(2) Advocate fine TACE therapy to reduce the heterogeneity of tumors leading to differences in TACE efficacy.
(3) TACE treatment (including cTACE and DEB-TACE) must follow a standardized and individualized protocol.
(4) Advocate comprehensive treatments such as TACE combined ablation therapy, radiation therapy, surgery, molecular targeted drugs, immunotherapy and antiviral therapy to further improve the efficacy of TACE.
(5) Liver cancer with portal vein trunk or primary branch carcinoma can be treated with intraportular stenting combined with iodine-125 particle therapy or direct puncture implantation of iodine-125 particles on the basis of TACE.
Radiation therapy
Radiation therapy is divided into external radiation therapy and internal radiation therapy. External beam therapy is the use of radiation rays (photons or particles) produced by radiotherapy equipment to irradiate tumors from outside the body. Endotherapy uses radionuclides that are implanted into a tumor through the body's tubes or through needles.
1. External beam therapy
(1) Indications for external beam radiation therapy
(1) Patients with CNLC I.a, partial I.b stage liver cancer who do not have indications for surgical resection or ablation or are reluctant to receive invasive therapy may consider SBRT as a treatment as appropriate [215-221] (evidence level 2, recommendation B). (2) In patients with CNLC STAGE II.a and II .b liver cancer, TACE combined with external beam radiation therapy can improve local control rates and prolong survival, which is better than that of TACE, sorafenib or TACE combined with sorafenib alone [208,216,222-226] (evidence level 1, recommendation B), which can be appropriately used. (3) In patients with CNLC stage III.a liver cancer, preoperative neoadjuvant radiation therapy or postoperative adjuvant radiation therapy can be resected with portal vein cancer suppository to prolong survival [95,227] (evidence level 2, recommendation C), palliative radiation therapy or combination radiation therapy with TACE and the like can be performed to prolong patient survival [208,225,226] (evidence level 2, recommendation B). (4) In patients with CNLC III .b liver cancer, some patients with oligometastatic foci can undergo SBRT to prolong survival time; ectopic lesions such as gonorrhea, lungs, bone, brain or adrenal glands, external radiation therapy can alleviate symptoms such as pain, obstruction or bleeding associated with metastases, and prolong survival time [209,228,229] (evidence level 3, recommendation A). (5) A part of the liver cancer patients who cannot be surgically removed Can be transformed into surgical resection after radiation therapy the tumor shrinks or descends into surgery [209,218] (evidence level 3, recommendation B); external radiation therapy can also be used to wait for preoperative bridging therapy for liver cancer liver transplantation [230]; postoperative pathology of liver cancer shows MVI, liver cancer surgical margin is narrow incision margin of 1 cm from the tumor ≤, postoperative auxiliary radiation therapy can reduce local recurrence of lesions or distant metastasis, prolong the survival of patients without tumors [231,232] (evidence, etc.). Level 4, C recommended).
(2) Contraindications to external radiation therapy
External radiation therapy is not recommended in patients with liver cancer, such as diffuse distribution of intrahepatic lesions or stage IV CNLC.
(3) Principles and main points of implementation of external radiation therapy
The principle of implementation of external radiation therapy for liver cancer is to comprehensively consider the dose of tumor exposure, the dose tolerated by the surrounding normal tissue, and the radiation therapy techniques used. The implementation points of external radiation therapy for liver cancer are: (1) When the radiation therapy plan is formulated, the intrahepatic lesions are defined in enhanced CT, and if necessary, various imaging data such as MRI images can be used to make use of the proliferative capacity of normal liver tissue, and some normal livers are retained from irradiation during radiation therapy, which may cause some normal liver tissue to gain hyperplasia. (2) The dose of liver cancer irradiation is closely related to the patient's survival time and local control rate, and basically depends on the tolerable dose of surrounding normal tissue [122,233]. Liver cancer radiation dose: stereotactic radiation therapy is generally recommended ≥ 45 to 60Gy/3 to 10 minutes (Fraction, Fx) [234], biological effective dose (BED) of radiation therapy is about ≥80Gy (α/β ratio is taken from 10Gy), lesions can obtain better radiotherapy efficacy [215]; conventional segmented radiation therapy is 50 to 75Gy; the dose of neoadjuvant radiation therapy portal venous cancer plug can be used 3Gy×6Fx[95]。 With image guided radiation therapy (IGRT) technical conditions, some intrahepatic lesions, cancer embolus or metastatic foci such as extrahepatic lymph nodes, lungs, and bones can be treated with low-segmented radiation therapy to improve a single dose, shorten the duration of radiation therapy, and the efficacy is not affected or even improved [235-237]; non-SBRT low-segmented external radiation therapy can be calculated using models, and the hepatocyte α/ β ratio of patients with HBV infection can be taken 8Gy, tumor cell α/β ratio of 10 to 15Gy as a dose conversion reference [122,209,238]. (3) The tolerated dose of normal tissues should be considered: radiation therapy segmentation, liver function Child-Pugh grading, normal liver (liver-tumor) volume, gastrointestinal congestion and coagulation function status (Appendix 7). (4) Radiation therapy technology for liver cancer: it is recommended to use three-dimensional conformal or intensity-modulated radiation therapy, IGRT or SBRT and other technologies. IGRT is superior to non-IGRT techniques [233], and tomography is appropriate for patients with multi-lesion liver cancer. Respiratory movement is a major cause of movement and deformation of liver tumors during radiation therapy, and a variety of techniques can be used to reduce the impact of respiratory movements, such as gating, real-time tracking, respiratory control, and abdominal compression combined with 4D-CT to determine the internal target area [239]. (5) There is a lack of higher-level clinical evidence to support the survival rate of proton radiation therapy in patients with liver cancer than photon radiation therapy [216].
(4) The main complication of external radiation therapy
Radiation-induced liver disease (RILD) is a dose-limiting complication of hepatic external radiation therapy, which is divided into two types: (1) typical RILD: alkaline phosphatase increased by >2 times the upper limit of normal value, no jaundice intraperitoneal effusion, hepatomegaly; (2) atypical RILD: alkaline phosphatase> 2 times the upper limit of normal value, alanine aminotransferase > upper limit or pre-treatment level of 5 times, liver function Child-Pugh The score decreased by ≥ 2 points, but there was no hepatomegaly and intraperitoneal effusion. Diagnosis of RILD must exclude liver tumor progression, viral or drug-induced clinical symptoms, and liver function impairment [209].
2. Proton beam radiation therapy and internal beam therapy
Proton radiotherapy (PBT) is similar to RFA for postoperative recurrent or residual liver cancer foci (<3 cm in size, ≤2 in number) [240] (evidence level 2, recommendation C).
Internal radiation therapy is a topical treatment of liver cancer, including yttrium-90 microsphere therapy, iodine-131 monoclonal antibody, radioactive iodized oil, iodine-125 particle implantation, etc. [47,228,229]. Sequential use of iodine-131-meduximab after RFA treatment for liver cancer reduces the rate of local recurrence after RFA treatment and improves patient survival [241] (evidence level 2, recommendation C). Particle implantation techniques include inter-tissue implantation, portal vein implantation, inferior vena cava implantation, and intrabiliary implantation for the treatment of intrahepatic lesions, portal vein cancer embolism, inferior vena cava cancer embolism, and intrabilangeal carcinoma or carcinoma thrombosis, respectively. Strontium chloride (89SrCl2) emits β rays that can be used to target the treatment of foci of bone metastases in liver cancer [242] (evidence level 3, recommendation C).
(1) In patients with CNLC STAGE III.A liver cancer, liver cancer with resectable portal artery carcinoma suppositories can be treated with preoperative neoadjuvant radiation therapy or postoperative auxiliary radiation therapy to prolong survival; for those who cannot be surgically resected, palliative radiation therapy can be performed, or radiation therapy can be combined with TACE and other therapy to prolong the survival of patients.
(2) In patients with CNLC III .b liver cancer, some patients with oligometastatic foci can undergo SBRT radiation therapy to prolong survival; external radiation therapy can also alleviate symptoms such as pain, obstruction or bleeding caused by lymph node, lung, bone, brain or adrenal metastases.
(3) Some patients can obtain surgical resection opportunities through radiation therapy conversion.
(4) Liver tumor irradiation dose: stereotactic radiation therapy is generally recommended ≥ 45 ~ 60Gy/3 ~ 10Fx, conventional segmented radiation therapy is generally 50 ~ 75Gy, and the irradiation dose is closely related to the survival of patients. Some intrahepatic lesions or extrahepatic metastases may be treated with low-segment radiation therapy to increase a single dose and shorten the duration of radiation therapy.
(5) The tolerated dose of normal tissues must be considered: radiation therapy segmentation, liver function Child-Pugh grading, normal liver (liver-tumor) volume, gastrointestinal stasis and coagulation function status, etc.
(6) IGRT is superior to three-dimensional conformal radiation therapy or intensity-modulated radiation therapy, and stereotactic radiation therapy must be performed under IGRT.
(7) Internal radiation therapy is a method of local treatment of liver cancer.
Systemic antitumor therapy
Systemic therapy, or systemic therapy, mainly refers to anti-tumor therapy, including molecular targeted drug therapy, immunotherapy, chemotherapy and traditional Chinese medicine therapy, etc.; in addition, it also includes the treatment of basic diseases of liver cancer, such as antiviral therapy, hepatoprotective choleretic and supportive symptomatic therapy.
Less than 30% of liver cancer patients at the time of first diagnosis are eligible for radical treatment due to the insidious onset of liver cancer, and systemic antineoplastic therapy plays an important role in the treatment of intermediate and advanced liver cancer. Systemic antineoplastic therapy can control disease progression and prolong survival in patients. The indications for systemic antineoplastic therapy are: (1) patients with CNLC stage III.a and .b liver cancer; (2) patients with CNLC stage II .b liver cancer who are not suitable for surgical resection or TACE treatment; and (3) patients with liver cancer who are resistant to TACE treatment or who have failed TACE treatment.
1. First-line anti-tumor therapy
(1) Atenizumab combined with bevacizumab
Atenizumab plus bevacizumab is approved for use in patients with unresectable liver cancer who have not previously received systemic therapy (evidence level 2, recommendation A). The results of the IMbrave150 global multicenter Phase III study [243,244] showed that the median survival time and progression free survival (PFS) in the attiolizumab and bevacizumab group were significantly longer than those in the sorafenib group, with a 34% lower risk of death and a 35% lower risk of disease progression. In the Chinese subpopulation, patients in the combination therapy group also had a significant clinical benefit, with a 47% lower risk of death and a 40% lower risk of disease progression compared with sorafenib. And combination therapy delayed patient-reported time of worsening of median quality of life. Common adverse reactions include hypertension, proteinuria, liver dysfunction, hypothyroidism, diarrhea, and decreased appetite.
(2) Sindili maclub combined with bevacizumab analogue (Dayoutong)
Sindilimab plus bevacizumab analogues (Dayoutong) has been approved in mainland China for first-line treatment of unresectable or metastatic liver cancer that has not previously received systemic antineoplastic therapy (evidence level 2, recommendation A). Orient32 Results of the National Multicenter Phase III study [245] show that the efficacy of sindilimab plus bevacizumab analogues (Dayoutong) was significantly better than that of the sorafenib group, and the risk of death decreased by 43% and the risk of disease progression by 44% in the combination treatment group compared with the sorafenib group. The safety of the combination regimen was good, and the most common adverse reactions in the combination treatment group were proteinuria, thrombocytopenia, elevated aspartate aminotransferase, hypertension, and hypothyroidism.
(3) Donafenib
Donafenib has been approved in mainland China for use in patients with unresectable liver cancer who have not previously received systemic antineoplastic therapy (evidence level 2, recommendation A). Compared with sorafenib, donafenib significantly prolonged median survival time and a 17% lower risk of death from advanced liver cancer; the median PFS in the donefenib and sorafenib groups was similar, but the donafenib group had good safety and tolerability [246]. The most common adverse reactions are hand-foot skin reactions, elevated aspartate aminotransferase, elevated total bilirubin, decreased platelets, and diarrhea.
(4) Lunvatinib
Lenvatinib is indicated in patients with advanced liver cancer of non-resectable liver function Child-Pugh Grade A (evidence level 1, recommendation A). Reflect Global Multicenter Clinical Phase III controlled study [247] where the intermediate survival time was not inferior to sorafenib, and the study achieved a non-inferior efficacy endpoint [hazard ratio (HR) was 0.92, 95% confidence interval (CI) was 0.79 to 1.06]. The median PFS in the renvatinib group was significantly better than that in the sorafenib group, with a 34% reduction in the risk of disease progression. Common adverse reactions include hypertension, proteinuria, diarrhea, decreased appetite, fatigue, and hand-foot syndrome.
(5) Sorafenib
Sorafenib was the earliest molecularly targeted drug used in the antitumor therapy of the liver cancer system. Multiple clinical studies have shown that sorafenib has a survival benefit for patients with advanced liver cancer in different countries and regions and in different liver disease backgrounds [248,249(] evidence level 1, recommendation A). Sorafenib can be used in patients with hepatic function Child-Pugh grade A or B, but the survival benefit is significant in patients with Child-Pugh Grade B compared to Child-Pugh Grade B liver function [250]. Efficacy and toxicity should be regularly evaluated and toxicity monitored during treatment. Common adverse effects are diarrhea, hand-foot syndrome, rash, hypertension, anorexia, and fatigue, usually occurring within 2 to 6 weeks of initiation of treatment. Blood pressure should be closely monitored during treatment, and liver and kidney function, HBV-DNA, blood routine, coagulation function, and urine protein should be checked regularly. During treatment, attention also needs to be paid to the risk of myocardial ischemia, and patients of particularly advanced age should be given the necessary monitoring and related tests.
(6) Systemic chemotherapy
The FOLFOX4 regimen is approved in mainland China for the first-line treatment of locally advanced and metastatic liver cancers that are not suitable for surgical resection or topical treatment [251,252] (evidence level 2, Recommendation A). In addition, arsenic trioxide has a certain palliative therapeutic effect on advanced liver cancer [253] (evidence level 4, recommended C), and attention should be paid to monitoring and preventing hepatobic toxicity in clinical applications.
(7) Progression of other first-line treatments
Immune checkpoint inhibitor therapy is widely used in the treatment of various solid tumors, and a single immune checkpoint inhibitor is less effective. At present, a number of clinical studies have confirmed that anti-hemogenesis therapy can improve the micro-environment of tumors, enhance the anti-tumor sensitivity of PD-1/PD-L1 inhibitors, and anti-angiogenesis combined immunotherapy can achieve synergistic anti-tumor effects. Two phase III studies (IMbrave150,0RIENT32) have been successful in the first-line treatment of advanced liver cancer with immune checkpoint inhibitors combined with macromolecular anti-angiogenic drugs (bevacizumab or biosimilars), and several clinical studies are underway in combination with small molecule anti-angiogenic drugs. These studies include but are not limited to: carellilizumab combined with apatinib Phase III clinical study (SHR-1210-III.-310), lenvatinib combined with papolili jujuzumab Phase III clinical study (LEAP 002), lunvatinib combined with navuliyu monoclonal antibody Phase I .b clinical study (Study 117), CS1003 (PD-1 monoclonal antibody) combined with lumpatinib Phase III clinical study (CS1003-305), Triprim monoclonal antibody combined with lunvatinib Phase III clinical study, etc. In addition, clinical studies in combination with other drugs of immune checkpoint inhibitors are also underway, such as the phase III clinical study of carellizumab combined with oxaliplatin-based systemic chemotherapy, the phase III clinical study of dovalibliumab and trimemumab (HIMALAYA), the phase III clinical study of sindilimab combined with IBI310 (anti-CTLA-4 monoclonal antibody).
2. Second-line anti-tumor therapy
(1) Rigofenib
Regofenib is approved for use in patients with liver cancer who have previously received sorafenib (evidence level 1, recommendation A). The International Multicenter Phase III RESORCE study evaluated the efficacy and safety of rigofenib in patients with liver cancer who progressed after treatment with sorafenib. The results showed that patients in the rigofenib group had a significantly reduced risk of death and a 54% lower risk of disease progression compared with placebo control. Common adverse reactions are hypertension, hand-foot skin reactions, fatigue and diarrhea. Its adverse effects are similar to those of sorafenib and, therefore, are not suitable for use in patients who cannot tolerate sorafenib.
(2) Apatinib
Apatinib mesylate is a small molecule targeted new drug independently developed in Mainland China, and has been approved as a single drug for patients with advanced liver cancer who have failed or become intolerable after receiving at least one-line systemic anti-tumor therapy in the past (evidence level 2, recommendation A). The results of the phase III clinical study of apatinib second-line treatment of advanced liver cancer in China [255] significantly prolonged the median survival time of patients with second-line or higher advanced liver cancer, with a 21.5% lower risk of death and a 52.9% decrease in the risk of disease progression compared with placebo. Common adverse reactions are hypertension, proteinuria, leukopenia, and thrombocytopenia. During use, the patient's adverse reactions should be closely followed, and the necessary dose adjustments need to be given according to the patient's tolerance.
(3) Carellizumab
Carellizumab has been approved for the treatment of patients with advanced liver cancer who have previously received sorafenib and/or chemotherapy with oxaliplatin-containing systems (evidence level 4, recommendation B). The results of a phase II clinical study of carelliltrumab in Chinese liver cancer treated with previous systemic antitumors showed that the ORR was 14.7%, the six-month survival rate was 74.4%, and the 12-month survival rate was 55.9%. Common adverse reactions are reactive telangi hyperplasia, elevated alanine/aspartate aminotransferase, hypothyroidism, and fatigue. Multiple clinical studies have shown a significant decrease in the incidence of reactive capillary hyperplasia after combined use of carellizumab and apatinib.
(4) Tirelizumab
Tirelizumab is approved for the treatment of patients with liver cancer who have undergone at least one systemic antitumor therapy (evidence level 4, recommendation B). The results of a global, multicenter phase II study (RATIONALE 208) aimed at evaluating the efficacy and safety of terelitizumab in the treatment of unresectable liver cancers that have previously received at least one systemic therapy showed [259] a median progression-free time of 2.7 months and a median survival time of 13.2 months, of which the median survival times of patients receiving first-line treatment and patients treated with second-line and above were 13.8 months and 12.4 months, respectively. The ORR of the total population was 13.3%, of which 13.8% of patients who received first-line systemic therapy and 12.6% of patients who received second-line and above treatment. The safety is good, and the main adverse reactions are elevated aspartate aminotransferase, elevated alanine aminotransferase, weakness and hypothyroidism. Currently, the international multicenter phase III study (RATIONALE 301) of tiralizumab in the first-line treatment of unresectable liver cancer patients with tirafenib and the Chinese multicenter phase II study (BGB-A317-211) of tiralizumab combined with resectable liver cancer patients with first-line treatment of non-resectable liver cancer are currently underway.
(5) Other second-line anti-tumor treatment options
The U.S. FDA has conditionally approved pambolizumab [260] (evidence level 3, recommendation B) and navuliyu monoclonal antibody plus ipicumab [261] (evidence level 4, recommendation B) for patients with liver cancer who have progressed after previous sorafenib therapy or who cannot tolerate sorafenib, cabotinib for liver cancer patients who progress after first-line systemic antineoplastic therapy [262] (evidence level 2, recommendation B), and remoruzumab for second-line treatment in patients with serum AFP levels ≥400 μg/L liver cancer [262] [262] and remolozumab for second-line therapy in patients with serum AFP levels ≥400 μg/L [262] [262] [262] [262] [262] 263,264] (Evidence Level 2, Recommendation B).
At present, the combination of immune checkpoint inhibitor therapy and targeted drugs, chemotherapy drugs, and topical therapy for the second-line treatment of liver cancer is also constantly being explored.
3. Other treatments
(1) Chinese medicine treatment
Under the guidance of the clinical medical system of integrated traditional Chinese and Western medicine [265], the clinical diagnosis and treatment mode of combining disease evidence [266] is adopted, and the chinese medicine prescription medicine, modern traditional Chinese medicine preparation and traditional Chinese medicine characteristic diagnosis and treatment technology are used, and the overall treatment is in the perioperative period, postoperative auxiliary treatment period, follow-up rehabilitation period, palliative period and other different periods of liver cancer, and cooperate with Western medical treatment to control symptoms, escort, prevent recurrence and metastasis and prolong survival.
1) Chinese medicine prescription drugs
(1) Perioperative application
Treatment objectives: to improve liver function and improve surgical tolerance.
Treatment principles: rational qi, liver thinning, spleen health.
Recommended prescription medicine: "Chongqing Tang Medical Essay" Qingfu Jindan plus and minus.
(2) Application of postoperative adjuvant therapy
Treatment goals: to reduce postoperative complications and accelerate postoperative recovery.
Treatment principles: straightening, strengthening the spleen, nourishing the blood.
Recommended prescription medicine: "Jisheng Fang" is added or subtracted from spleen soup.
(3) Follow-up application during rehabilitation
Treatment goals: to improve quality of life and prevent tumor recurrence and metastasis.
Treatment principles: liver thinning, spleen strengthening, straightening.
Recommended prescription medicine: "Taiping Huimin and Pharmacy Bureau Fang" loose scattering plus and minus.
(4) Application of the palliative period
Treatment objectives: attenuation and efficiency, prolong survival.
Treatment principles: yin nourishment, soft firmness, stasis.
Recommended prescription medicine: "Liuzhou Medical Words" has always been fried with "The Complete Collection of Jiang Chunhua" to benefit the liver and clear the soup plus or minus.
2) Modern Chinese medicine preparations
In addition to Chinese medicine decoction into decoctions in Chinese medicine, several modern Chinese medicine preparations [such as locust ear granules [136] (evidence level 2, recommendation A), hua toxin combined detoxification granules [267] (evidence level 2, recommendation B)] have been used for adjuvant therapy after surgical resection of liver cancer. In addition, locust ear granules, epimedium, olive eleutherene, toadin, Conlet, Kangai, Hepatic Fule, Golden Dragon Capsules, Eddie, Crow Gall Oil, Compound Cantharid Capsules and Cidan Capsules are used for the treatment of advanced liver cancer [268-275], which have certain efficacy, and patient compliance, safety and tolerance are good, but further standardized clinical studies are needed to obtain high-level evidence-based medical evidence.
3) Characteristic diagnosis and treatment technology of traditional Chinese medicine[267-275]
(1) Acupuncture treatment
According to the condition and clinical reality, you can choose to apply body needles, head needles, electric needles, ear needles, wrist and ankle needles, eye needles, moxibustion methods, acupuncture point threads, acupuncture points, ear acupuncture and cupping methods.
Acupuncture treatment takes liver Yu and Foot Sanli as the main acupuncture points, with Yangling Spring, Period Gate, Zhangmen, Sanyin Jiao, etc.; acupuncture points are applied to Zhangmen, Period Gate, Liver Yu, Neiguan, Gongsun Main Acupuncture, and those in pain are matched with Waiguan, Zusanli, Yangling Spring; Ascites with Qihai, Sanyin Jiao, Yinling Spring, etc.
(2) Other treatments
According to the condition, chinese medicines such as blood circulation and stasis, heat and detoxification are used as appropriate, and traditional Chinese medicines and proprietary Chinese medicines are used, and external treatment, traditional Chinese medicine bubble washing, And Chinese medicine fumigation are carried out.
(2) Antiviral therapy and other hepatoprotective therapy
In patients with HBV-infected liver cancer, oral nucleoside analogue antiviral therapy should be present throughout the treatment process. If the HBV-DNA level is high before surgery, and the Alanine aminotransferase level > 2 times the upper limit of normal value, antiviral and hepatoprotective therapy can be given first, and then surgical resection can be performed after the liver function improves to improve the safety of surgery; for those with high HBV-DNA levels but no obvious abnormalities in liver function, effective antiviral therapy can be given as soon as possible. If hepatitis B surface antigen (HBsAg) is positive, the use of potent and low-resistance entecavir, tenofovir ester, or propofol tenofovir [211] is recommended (evidence level 1, recommendation A). Antiviral therapy with DAAs is recommended for HCV-associated liver cancer with HCV-associated liver cancers with HCV-positive [276,277] (evidence level 1, recommendation A).
Liver cancer patients in the natural course of disease or treatment may be accompanied by abnormal liver function, should be timely and appropriate use of anti-inflammatory, antioxidant, detoxification, choleretic and hepatocyte membrane repair protective effects of liver protection drugs, such as magnesium isoliglycinate injection, diammonium glycyrrhizinate, compound glycyrrhizin, bicyclool, silymarin, reduced glutathione, adenosylmethionine, ursodeoxycholic acid, polyene phosphatidylcholine and usstatin. These drugs can protect liver function, improve treatment safety, reduce complications and improve quality of life.
(3) Symptomatic supportive treatment
Patients with liver cancer often have cirrhosis, enlarged spleen, and one or more lines of hemocytopenia due to antitumor therapy, etc., and may be considered for blood product transfusion or drug therapy. Patients with neutropenia may be given granulocyte colony stimulating factor (G-CSF), including polyethylene glycol-recombinant human G-CSF and recombinant human G-CSF as appropriate [278]. Patients with hemoglobin < 80 g/L may receive infusion of erythrocyte suspensions or medications, including iron, folic acid, vitamin B12, and erythropoietin, as appropriate. Platelet transfusions may be considered as appropriate in patients with thrombocytopenia, and to reduce platelet transfusions, platelet counts can be increased in non-emergency settings using recombinant human thromboplastin or thromboplastin receptor agonists [279].
Patients with advanced liver cancer should be given optimal supportive care, including aggressive analgesia, correction of hypoalbuminemia, enhanced nutritional support, control of blood glucose levels in patients with diabetes mellitus, and management of complications such as ascites, jaundice, hepatic encephalopathy, gastrointestinal bleeding, and hepatorenal syndrome. For patients with symptomatic bone metastases, bisphosphonates may be used. In addition, moderate rehabilitation exercises can enhance the immune function of patients. At the same time, it is necessary to pay attention to the psychological intervention of patients, enhance the confidence of patients to overcome the disease, transform negative psychology into positive psychology, and reduce depression and anxiety through soothing treatment to make them feel safe and comfortable.
4. Evaluation of the efficacy of systematic anti-tumor therapy
For patients treated with systematic antineoplastic therapy, most of them currently use the response evaluation criteria in solid tumor (RECIST) 1.1 for efficacy evaluation. For patients receiving antivascular molecularly targeted therapy, mRECIST can be used in combination. The immune RECIST (iRECIST) criteria for evaluating the immune efficacy of solid tumors can also be applied to patients receiving immune checkpoint inhibitors [280].
(1) Indications for systemic antitumor therapy: CNLC III.a, III.b liver cancer patients, CNLC II .b liver cancer patients who are not suitable for surgical resection or TACE treatment, TACE treatment resistance or TACE treatment failure of liver cancer patients.
(2) First-line anti-tumor therapy options can be selected from atenizumab plus bevacizumab, sindilimab plus bevacizumab analogue (Dayoutong), donafenib, lenvatinib, sorafenib or systemic chemotherapy containing oxaliplatin.
(3) Second-line anti-tumor treatment options, in the mainland can choose rigofenib, apatinib, carellizumab or terelizumab.
(4) According to the needs of the condition, traditional Chinese medicine can be applied, such as locust ear granules.
(5) At the same time as anti-tumor therapy, antiviral therapy should run through the whole process of treatment, and at the same time, hepatoprotective choleretic and supportive symptomatic therapy should be carried out as appropriate.
Treatment of spontaneous rupture of liver cancer
Spontaneous rupture of liver cancer is a potentially fatal complication of liver cancer, and the case fatality rate in hospitals with simple conservative treatment is extremely high, but it is not a determinant of long-term survival of patients. Therefore, after the initial rescue is successful, the patient's hemodynamics, liver function, systemic condition, and tumor resectability should be fully evaluated, and an individualized treatment plan should be formulated [281-285].
1. Surgical resection is preferred in patients with resectable liver tumors, good liver reserve function, and stable hemodynamics [286,287] (evidence level 3, recommendation A).
2. TaE [288] can be selected for patients with poor liver reserve function, hemodynamic instability, and no surgical conditions (evidence level 4, recommendation B).
3. Due to emergency conditions, liver function and liver tumor conditions can not be fully assessed, TAE can be first, combined with follow-up evaluation and then select the corresponding treatment regimen, if you can perform secondary surgical resection can obtain a significant survival benefit [286] (evidence level 3, recommendation A).
4. Spontaneous rupture of liver cancer is a high-risk recurrence factor after surgery, and intraoperative irrigation of the abdominal cavity should be adequately given and adjuvant therapy should be given after surgery; patients with simple peritoneal metastases after surgery may be considered for aggressive radical resection [289] (evidence level 3, recommendation C).
Transferred from the Medical Administration