Chinese expert consensus on refined diagnosis, treatment, and management of advanced primary liver cancer (2023 edition)

Abstract

Hepatocellular carcinoma (HCC), commonly known as primary liver cancer, is a major cause of malignant tumors and cancer-related deaths in China, accounting for approximately 85% of all cancer cases in the country. Several guidelines have been used to diagnose and treat liver cancer. However, these guidelines provide a broad definition for classifying advanced liver cancer, with an emphasis on a singular approach, without considering treatment options for individual patients. Therefore, it is necessary to establish a comprehensive and practical expert consensus, specifically for China, to enhance the diagnosis and treatment of HCC using the Delphi method. The classification criteria were refined for Chinese patients with HCC, and the corresponding optimal treatment regimen recommendations were developed. These recommendations took into account various factors, including tumor characteristics, vascular tumor thrombus grade, distant metastasis, liver function status, portal hypertension, and the hepatitis B virus replication status of patients with primary HCC, along with treatment prognosis. The findings and recommendations provide detailed, scientific, and reasonable individualized diagnosis and treatment strategies for clinicians.

1. Introduction

Primary liver cancer, often referred to as hepatocellular carcinoma (HCC), is a prevalent contributor to malignant tumors and cancer-related fatalities in China, accounting for approximately 85% of all cancer cases in the country.¹ Approximately 39.0%–53.6% of patients with newly diagnosed liver cancer are found to be at the advanced stage annually, characterized by a refractory condition and a short survival.² Furthermore, most patients with liver cancer in China commonly experience coexisting hepatitis virus infection and/or cirrhosis, often resulting in portal hypertension. Moreover, the distinct epidemiological features, such as a large tumor burden and relatively advanced disease stage, imply that foreign guidelines and recommended treatment approaches may not be optimally applicable for diagnosing and treating patients with liver cancer in China. The latest update report on the 2022 survival analysis from the China liver cancer survey revealed varied median overall survival (mOS) among patients at various stages of liver cancer. These variations were outlined in the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition), also known as the China Liver Cancer (CNLC) guidelines, issued by the National Health Commission of the Peoples Republic of China.³ The mOS for patients at an advanced stage (stage III–IV) is 14.9 months, with a 5-year survival rate of only 28.2%. Nonetheless, the survival duration of patients with stage III disease is 6–48 months, whereas that of patients with Barcelona Clinic Liver Cancer staging (BCLC) stage C is 4–30 months.4, 5, 6 Therefore, patients with stage III liver cancer (BCLC stage C) require a more precise grading system and a personalized management strategy to receive individualized diagnostic and treatment recommendations.

The current versions of guidelines from the European Association for the Study of the Liver, National Comprehensive Cancer Network, Chinese Society of Clinical Oncology (CSCO), and CNLC for the diagnosis and treatment of liver cancer have collectively played a significant role in advancing the diagnosis and treatment of primary liver cancer in China. However, these specifications, guidelines, and consensus statements provide broad definitions for the classification of advanced liver cancer, often emphasizing a single treatment approach without elucidating the preferred hierarchy of diverse treatment options for individual patients.

Because the CNLC guidelines are better suited for staging and treatment recommendations for liver cancer in China than other guidelines, this consensus further refined the classification and management of stage III liver cancer based on these guidelines. Under the fundamental framework of the CNLC guidelines and along with the most recent clinical study data and liver cancer reports, the advanced liver cancer population was further subdivided. Evidence of inappropriate levels was deliberated and voted upon by an expert panel to determine the recommended opinions. Therefore, this study aimed to establish a more comprehensive and practical expert consensus that aligns with the specific national circumstances in China, focusing on the enhanced diagnosis and treatment of advanced primary liver cancer. An optimal recommended treatment strategy was developed by incorporating the recently published guidelines for hepatocarcinoma-related procedures such as transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), radiotherapy, conversion to resectability, targeted therapy, and immunotherapy. This consensus is anticipated to enhance the diagnosis and treatment of liver cancer, ensuring medical quality and safety, and optimizing the use of medical resources in China.

2. Study method

This consensus aligns with the CNLC guidelines (2022 edition) and uses the Grading of Recommendations, Assessment, Development, and Evaluation methodology to assess evidence,³ which is categorized into five grades (grades 1–5) and three recommendation strengths such as strong (grade A), moderate (grade B), and weak recommendations (grade C). To address the pressing challenges frequently encountered in clinical practice, the Delphi method was used to gauge the strength of expert consensus to determine recommendations for patients who lack sufficient evidence from existing clinical studies. The Delphi method is a systematic approach used to evaluate expert opinions on consensus-related issues through multiple rounds of anonymous written inquiries. Following iterative consultation, summarization, modification, and statistical analysis, the final results are compiled.⁷

The Delphi method for this consensus was conducted as follows: (i) compilation of issues with insufficient clinical evidence in the initial draft consensus; (ii) establishment of an expert panel; (iii) in the first round of discussion, identification of controversial issues using various media, such as email; and (iv) in the second round, a review of summarized issues and initiation of consensus formation. The first two rounds of discussion formed the basis for subsequent deliberation through qualitative analysis and clarification of issues using open-ended questions or the Likert scale. Others include the following: (v) in the third round of discussion, the expert panel should review the judgment made to that point, forming a consensus; (vi) in the fourth round of discussion (initiated based on the results of the first three rounds), the expert panel should make a final judgment on any previous objections and provide explanations; and (vii) the conclusion was drawn, and the consensus results were analyzed and summarized using standard statistical analysis tools. The determination of validity was contingent on the response rate, with the requirement that agreement should be ≥ 75% to establish a consensus conclusion.⁸ In addition, this consensus included a supplemental study to explore the preferences of experts for clinical practice through multiple-choice questions.

3. Existing clinical classification criteria for advanced liver cancer and issues

Liver cancer staging includes six factors: the number of liver tumors, their size, vascular invasion, extrahepatic metastasis, Child-Pugh classification, and performance status (PS). According to the CNLC guidelines,³ advanced liver cancer is categorized into two stages: (i) stage IIIa: PS 0–2, Child-Pugh class A/B, regardless of tumor local conditions, with visible vascular tumor thrombus on imaging but without extrahepatic metastasis; and (ii) stage IIIb: PS 0–2, Child-Pugh class A/B, regardless of tumor local conditions, with visible vascular tumor thrombus on imaging and extrahepatic metastasis and corresponding BCLC stage C: portal vein invasion and/or extrahepatic spread, good liver function, and PS 1–2. The BCLC stage C definition is more comprehensive than the classification in the CNLC guidelines because it encompasses local tumor metastasis. The above-mentioned guidelines offer comprehensive definitions for advanced liver cancer but primarily concentrate on specific treatments for tumor thrombus and extrahepatic metastasis without specifying preferred treatment options. The location and extent of portal vein tumor thrombus (PVTT) in patients with liver cancer significantly influence prognosis. Similarly, treatment decisions and OS are influenced by distinct factors, such as the organs involved in extrahepatic metastasis and metastatic tumor numbers. Simultaneously, Child-Pugh class B also varies in liver function. Patients classified as Child-Pugh class B7 tend to have a well-compensated liver function, whereas those with B8/9 exhibit poorer liver function, leading to increased incidences of liver-related adverse reactions, adverse reactions to tumor treatment, and ultimately, a less favorable survival and prognosis (6.0–9.0 months).^9,10 The current CSCO and Chinese expert consensus on multidisciplinary treatment of liver cancer guidelines suggest the use of Child-Pugh class B7 as the threshold when determining treatment options.¹¹ In addition, phase III clinical trials for systemic liver cancer treatment, such as IMbrave150,¹² HIMALAYA,¹³ LEAP-002,¹⁴ ORIENT-32,¹⁵ ZGDH3,¹⁶ and AHELP,¹⁷ typically include patients with Child-Pugh class A or those below B7 as part of their inclusion criteria. Hence, this consensus suggests a more detailed classification, specifically Child-Pugh class B7. It emphasizes considerations related to portal hypertension, hepatitis B virus (HBV), DNA/hepatitis C virus (HCV), and RNA replication status, as well as the diagnostic details, treatment, and management to develop a more refined classification plan for advanced liver cancer.

Recommendation 1: Child-Pugh class B7 is recommended as the primary threshold for precisely classifying the liver function status of advanced liver cancer (with a 95% consensus agreement among experts).

Second, comorbid PVTT is a major adverse factor affecting the prognosis of liver cancer and is significant in the clinical diagnosis and treatment of liver cancer.¹⁸ The current PVTT classification criteria mainly include the Japanese VP classification and Cheng's classification proposed by Professor Cheng Shuqun in China (Table 1).^19,20 In contrast to the Japanese VP classification, Cheng's classification separately categorizes microvascular tumor thrombus (as I₀), combines clinically indistinguishable VP1 and VP2 into type I, and further refines VP4 with multigrade portal vein involvement as type III/IV, specifically emphasizing the mesenteric vein tumor thrombus (type IV). Cheng's classification shows a strong clinical prognostic correlation and facilitates the selection of diagnosis and treatment options.21, 22, 23, 24 Therefore, this consensus recommends Cheng's classification as a reference criterion for the precise classification of PVTT in advanced liver cancer.

Table 1.

Difference between Cheng's and Japanese VP classifications of comorbid portal vein tumor thrombus in hepatocellular carcinoma.

Portal vein branches	Terminal branch	Grade 3	Grade 2	Grade 1	Trunk	Superior mesenteric vein
Cheng's classification	Microvascular tumor thrombus	I	I	II	III	IV
Japanese VP classification		VP1	VP2	VP3	VP4	VP4

Recommendation 2: Cheng's classification is recommended as the reference criterion for the precise classification of advanced liver cancer with PVTT (with a 100% consensus agreement among experts).

The presence of extrahepatic metastasis in liver cancer also constitutes a major adverse factor affecting disease prognosis. Furthermore, it plays an important role in the clinical diagnosis and treatment of liver cancer. The concept of oligometastasis is commonly applied in the classification of solid tumors for diagnostic and treatment purposes. It was defined as having ≤5 metastatic/recurrent lesions, ≤2 involved organs, and representing an intermediate state with mild biological invasiveness, somewhere between localized primary tumors and extensive metastases.²⁵ The concept of liver cancer oligometastasis has not yet been established; however, numerous small-scale clinical studies have been conducted to investigate treatments for this condition.²⁶

Recommendation 3: The definition of liver cancer oligometastasis (≤5 metastatic/recurrent lesions and ≤2 involved organs) is recommended as the reference criteria for characterizing extrahepatic metastatic lesions and providing treatment decision guidelines for the precise classification of advanced liver cancer (with a 95% consensus agreement among experts).

Recommendation 4: Based on the above evidence, the recommended classification criteria for advanced liver cancer were as follows (see Fig. 1 for the specific staging route):

Fig. 1.

Staging and treatment routes of refined diagnosis, treatment, and management of advanced primary liver cancer. Systemic anti-tumor drugs include first-line therapeutic options: atezolizumab combined with bevacizumab/sintilimab combined with bevacizumab/camrelizumab combined with apatinib/tremelimumab combined with durvalumab/systemic chemotherapy based on donafenib/lenvatinib/sorafenib/oxaliplatin; second-line therapy options: regorafenib/apatinib/pembrolizumab/camrelizumab/tislelizumab. Abbreviations: HAIC, hepatic arterial infusion chemotherapy; HCC, hepatocellular carcinoma; MDT, multidisciplinary team; PS, performance status; PVTT, portal vein tumor thrombus; TACE, transarterial chemoembolization.

Stage IIIa₁: PS 0–2, Child-Pugh class A/B (≤7 points), PVTT (type III), tumors confined to the hemiliver and ≤3 in number, with sufficient residual liver volume and function, and without evidence of extrahepatic metastasis.

Stage IIIa₂: PS 0–2, Child-Pugh class A/B (≤7 points), PVTT (type I–II), >3 tumors, or extension beyond one hemiliver, and without evidence of extrahepatic metastasis.

Stage IIIa₃: PS 0–2, Child-Pugh class A/B (≤7 points), PVTT (type III–IV)/vena cava tumor thrombus, and without evidence of extrahepatic metastasis.

Stage IIIa₄: PS 0–2, Child-Pugh class B (>7 points), PVTT (type I–IV) and without evidence of extrahepatic metastasis, irrespective of tumor condition.

Stage IIIb₁: PS 0–2, Child-Pugh class A/B (≤7 points), and the presence of oligometastasis in extrahepatic lesions, regardless of tumor conditions and vascular tumor thrombus.

Stage IIIb₂: PS 0–2, Child-Pugh class A/B (≤7 points), and presence of extrahepatic lesion metastasis extending beyond the definition of oligometastasis, regardless of tumor conditions and presence of vascular tumor thrombus.

Stage IIIb₃: PS 0–2, Child-Pugh class B (>7 points), with extrahepatic lesion metastasis, regardless of tumor conditions and presence of vascular tumor thrombus.

4. Refined diagnosis, treatment, and management of patients with advanced liver cancer

4.1. Classification and management of patients with stage IIIa

4.1.1. Diagnosis and treatment of patients with stage IIIa₁

Patients with liver cancer and PVTT type I–II can potentially be cured with surgical resection. Simultaneous resections of the primary tumor and thrombus can effectively alleviate portal venous pressure. Studies reported that surgical resection can result in significantly better survival outcomes than other treatment methods.^27,28

For patients with Child-Pugh class A or low-score class B (≤7 points) liver function and PVTT (type I–II), if the tumor is confined to the hemiliver and the residual liver volume and function are sufficient, that is, the future liver remnant must account for more than 40% (in patients with chronic liver disease, parenchymal injury, or cirrhosis) or more than 30% (in patients without fibrosis or cirrhosis) of the standard liver volume, and the indocyanine green retention at 15 mins must be less than 30%, surgical resection of the tumor with PVTT and the involved portal vein may be considered, followed by TACE therapy, portal vein chemotherapy, or other systemic anti-tumor therapy (evidence level 3, recommendation B).29, 30, 31

High-quality evidence for neoadjuvant therapy in liver cancer is currently limited. Various pre- and perioperative neoadjuvant therapeutic regimens for surgically resected liver cancer are actively being investigated. Preliminary results from various small-scale neoadjuvant studies have been reported as follows: patients with PVTT type I–II could benefit from preoperative TACE;³² neoadjuvant HAIC decreased the recurrence rate among patients at risk of liver cancer recurrence, with a 5-year survival rate of 100%.³³ Patients treated with immunotherapy combined with targeted therapy followed by surgery exhibited a decreased risk of postoperative tumor recurrence and death by 76% and 77%, respectively.³⁴ Several studies have revealed that preoperative three-dimensional conformal radiotherapy is associated with improved long-term survival in patients with liver cancer compared with surgery alone.^35,36 In the phase II trial utilizing camrelizumab combined with apatinib in the perioperative phase, the objective response rate reached 33.3%.³⁷ Similarly, the results of a perioperative phase II clinical trial using nivolumab (n = 13) or nivolumab combined with ipilimumab (n = 14) demonstrated that the median progression-free survival (mPFS) in the combined treatment group was 19.5 months, significantly superior to that of the single-agent group.³⁸ The clinical trials mentioned above revealed the achievements of drugs and local therapy in the field of neoadjuvant therapy. However, the postoperative advantages of these approaches should still be validated through extensive clinical studies. Following a comprehensive evaluation by a multidisciplinary team (MDT), the risk of postoperative recurrence and metastasis was assessed, leading to the introduction of neoadjuvant therapy.

Postoperative systemic combination therapy and/or local treatment options are recommended to reduce the risk of postoperative recurrence and enhance the prognosis. In patients with liver cancer and PVTT type I–II, various postoperative adjuvant therapies have shown promise: adjuvant therapy with atezolizumab combined with bevacizumab after radical resection resulted in a 33% lower disease recurrence rate than that of the monitoring group.³⁹ Postoperative administration of sorafenib significantly extended the OS of patients and reduced the tumor recurrence rate compared with that in the control group. However, large-scale clinical studies are required for confirmation; combining TACE with lenvatinib for postoperative adjuvant therapy in patients with a high risk of liver cancer recurrence may, compared with TACE alone, significantly prolong median disease-free survival (mDFS).⁴⁰ Postoperative adjuvant radiotherapy, or HAIC, also provided survival benefits to patients (evidence level 2, recommendation B);41, 42, 43, 44 for patients with PVTT, postoperative transcatheter portal vein chemotherapy combined with TACE may also prolong the OS of patients (evidence level 2, recommendation A).⁴⁵

Surgical resection with intraoperative ablation is indicated for the treatment of multiple liver cancers (evidence level 4, recommendation C).46, 47, 48

To maximize the likelihood of achieving radical resection, patients with liver cancer and bile duct tumor thrombus may undergo a combined procedure involving the resection of both the liver tumor and affected bile duct (evidence level 3, recommendation C).49, 50, 51

Recommendation 5: Patients with the following criteria are recommended for surgical resection as the preferred treatment option: Child-Pugh class A or B (≤7 points), tumors confined to the hemiliver and ≤3 in number, resectable primary lesions, adequate residual liver volume and function, PVTT type I–II, and PS 0–1 (with a 91% consensus agreement among experts).

Recommendation 6: Patients with PVTT type I–II are recommended to undergo preoperative three-dimensional conformal radiotherapy or postoperative adjuvant TACE, radiotherapy, or systemic anti-tumor drugs. This process is aimed at delaying or reducing postoperative recurrence (with a 91% consensus agreement among experts).

4.1.2. Diagnosis and treatment of patients with stage IIIa₂

For patients in Child-Pugh class A or B (≤7 points) who also have PVTT (type I–II), local TACE treatment should be initiated first if these patients have >3 tumors or if the tumors extend beyond a single hemiliver.⁵² This approach is recommended to maximize tumor inactivation and safeguard liver function (evidence level 2, recommendation A).

Combining intraportal stent implantation with an iodine-125 seed strip or iodine-125 seed portal vein stent implantation can be used based on TACE (evidence level 2, recommendation B);⁵³ TACE combined with microwave ablation can significantly prolong the OS and PFS of patients with liver cancer (evidence level 2, recommendation B).⁵⁴

TACTICS, a phase II study, demonstrated that TACE combined with sorafenib significantly improved mPFS compared with TACE alone (25.2 vs. 13.5 months). However, no significant improvement was observed in the survival rate.⁵⁵ Retrospective studies have also confirmed that TACE combined with the molecular targeted drug apatinib is more effective than TACE alone.^56,57 Further conclusions require confirmation through large-scale, multicenter, randomized controlled studies.

Recommendation 7: Patients in Child-Pugh class A or B (≤7 points) with unresectable primary lesion, PVTT type I–II, >3 tumors, tumors extending beyond a single hemiliver, and PS 0–1 are recommended to receive local TACE first, combined with ablation, radiotherapy, and systemic anti-tumor drug therapy (with a 91% consensus agreement among experts).

Recommendation 8: For patients who poorly responded to TACE alone, TACE combined with systemic anti-tumor drug therapy should be initiated earlier (with a 95% consensus agreement among experts).

4.1.3. Diagnosis and treatment of patients in stage IIIa₃

For patients in Child-Pugh class A or B (≤7 points) with PVTT (type III–IV), oxaliplatin-based HAIC is more effective than TACE if hilar collateral circulation is good.⁵⁸ In addition, sorafenib combined with HAIC significantly improves the survival of patients with liver cancer and PVTT (type III–IV) compared with sorafenib alone (evidence level 1, recommendation A).⁵⁹

For patients in Child-Pugh class B (≤7 points) with PVTT (type III–IV), local combined radiotherapy can also be considered (evidence level 2, recommendation B).60, 61, 62

Recommendation 9: Patients in Child-Pugh class A or B (≤7 points) with unresectable primary lesions, PVTT type III–IV, well-developed hilar collateral circulation, and PS 0–1 may be treated with HAIC (with an 86% consensus agreement among experts). The combination drug therapy and management regimen should follow the guidelines outlined for the systemic treatment of patients in stage IIIb₂.

Recommendation 10: Patients in Child-Pugh class A or B (≤7 points) with liver cancer and unresectable primary lesion, PS 0–1, and PVTT III–IV may consider radiotherapy for the primary lesion and PVTT (with a 91% consensus agreement among experts). For the combined drug therapy and management regimen, it is advisable to refer to the guidelines provided for the systemic treatment of patients in stage IIIb₂.

4.1.4. Diagnosis and treatment of patients in stage IIIa₄

For patients in Child-Pugh B8/9 with PVTT, liver protection and supportive treatment are recommended to improve liver function to reach Child-Pugh B7 before proceeding with tumor-related interventions. During this stage, Icaritin (Epimedium genus) can be considered to prolong and improve the OS of the liver cancer-enriched population (with ≥2 of the following characteristics: alpha-fetoprotein (AFP), ≥400 ng/mL; tumor necrosis factor-alpha (TNF-α), <2.5 pg/mL; and interferon-gamma (IFN-γ), ≥7.0 pg/mL) (evidence level 1, recommendation B).^63,64 Additionally, the use of modern traditional Chinese medicine (TCM) formulations specifically indicated for liver cancer, such as elemene injection/oral solution and Xiaoaiping (Tongguanteng) injection/oral solution,^65,66 may be considered (evidence level 2, recommendation A).

The condition of a patient can also be assessed based on their actual liver function. Following an MDT consultation, systemic anti-tumor drug therapy can be administered when deemed necessary in combination with other local treatment options. Throughout the process, hepatologists closely monitor the alterations in liver function indicators.

Recommendation 11: For patients with advanced liver cancer defined as Child-Pugh class B (>7 points), the restoration of liver function to Child-Pugh B7 should be prioritized before initiating the anti-tumor treatment. During this phase, incorporating Icaritin treatment can be considered, or the treatment approach can be determined following consultation with an MDT, including hepatologists (with a 95% consensus agreement among experts).

4.2. Classification and management of patients in stage IIIb

Stage IIIb liver cancer is primarily characterized by the occurrence of extrahepatic metastasis. Its treatment options differ depending on the specific metastatic organs and the number of metastases. This part focuses on the treatment recommendations for metastases. The management of primary liver tumors can be guided by the previously mentioned recommendations for stage IIIa.

4.2.1. Diagnosis and treatment of patients in stage IIIb₁

Systemic treatment should be prioritized for patients with Child-Pugh class A or B (≤7 points) with oligometastatic lesions; however, if the disease stabilizes, local treatment should be considered to further enhance therapeutic efficacy. Radiotherapy can significantly improve the survival of patients with liver cancer and lymph node metastasis. Previous studies have shown a significant difference in the survival of patients with liver cancer with lymph node metastasis between the two groups: with and without external radiotherapy (mOS: 9.4 vs. 3.3 months).⁶⁷ In addition, patients with ≤5 adrenal metastases,⁶⁸ lung metastases,⁶⁹ or brain metastases may be administered systemic drug therapy combined with radiotherapy to relieve symptoms of metastases and prolong the survival time (evidence level 3, recommendation A).⁷⁰

Based on data from a study with large number of patients, although the postoperative OS for stages IIIa and IIIb is not satisfactory, surgical resection can still be beneficial for some patients in the absence of other effective treatment methods (evidence level 4, recommendation C).⁷¹ For patients with hilar lymph node metastasis, resection of the tumor with hilar lymph node dissection or postoperative external radiotherapy can be considered. Surgical resection can also be considered if the surrounding organs are invaded and can be resected together.⁷²

Recommendation 12: For patients with Child-Pugh class A or B (≤7 points) and extrahepatic oligometastasis, active local treatment is recommended (with an 86% consensus agreement among experts).

4.2.2. Diagnosis and treatment of patients in stage IIIb₂

Advanced liver cancer often coexists with cirrhosis and increased portal vein pressure, and thereby, the risk of gastrointestinal bleeding caused by antiangiogenic drugs should be considered. The following first-line treatments are recommended for patients with Child-Pugh class A or B (≤7 points) with multiple extrahepatic metastases: atezolizumab combined with bevacizumab (evidence level 1, recommendation A),73, 74, 75 sintilimab combined with bevacizumab (evidence level 1, recommendation A),¹⁵ and camrelizumab combined with apatinib (evidence level 1, recommendation A).⁷⁶ Others include tremelimumab combined with durvalumab (evidence level 1, recommendation A),⁷⁷ donafenib (evidence level 1, recommendation A),^16,78 lenvatinib (evidence level 1, recommendation A),⁷⁹ sorafenib (evidence level 1, recommendation A),^80,81 and oxaliplatin-based systemic chemotherapy (evidence level 1, recommendation A).^82,83 Patients with liver cancer complicated with HBV infection and AFP of >400 ng/mL are also advised to undergo a combination treatment with lenvatinib and pembrolizumab (evidence level 1, recommendation A).⁸⁴

In addition, phase III clinical studies regarding immunotherapy combined with antiangiogenic drugs (such as toripalimab combined with lenvatinib/bevacizumab and penpulimab combined with anlotinib), a phase III clinical study involving immunotherapy combined with chemotherapy (camrelizumab combined with FOLFOX4), and a phase III clinical study examining the combined immunotherapy approach (nivolumab combined with ipilimumab) have completed enrollment or are ongoing. These studies hold the potential for promising outcomes.

Comprehensive evaluation of several factors should be considered in selecting a second-line and subsequent systemic treatment strategy for liver cancer, including the first-line treatment regimen, mode of progression (systemic treatment intolerance or imaging progression), AFP level, liver function compensation status, patient compliance, and pharmacoeconomics. For patients on progression or who exhibited intolerance to first-line systemic drugs such as sorafenib and lenvatinib, several second-line treatment options are recommended, given that they align with the following specified indications: regorafenib (evidence level 1, recommendation A),⁸⁵ apatinib (evidence level 1, recommendation A),¹⁷ pembrolizumab (evidence level 3, recommendation A),^86,87 camrelizumab (evidence level 3, recommendation B),⁸⁸ and tislelizumab (evidence level 3, recommendation B).⁸⁹ For patients undergoing first-line combination immunotherapy, no large-scale phase III randomized controlled prospective clinical study data exists regarding second-line drug treatment regimens. The following questions arise: are the existing second-line treatment options still valid? Can the existing first-line tyrosine kinase inhibitors become the second-line treatment after immunotherapy? Future studies should address these points. The findings from retrospective and small-scale studies revealed that patients tended to have greater benefits from continued combination immunotherapy in their subsequent lines of treatment (evidence level 3, recommendation C).90, 91, 92

For patients with well-controlled extrahepatic lesions following systemic treatment, TACE is recommended for hepatic lesions. Some patients exhibiting vascular invasion can be treated with HAIC based on systemic treatment.⁹³

Recommendation 13: Patients categorized under Child-Pugh class A or B (≤7 points) with multiple extrahepatic metastases are best suited for systemic therapy. Decisions regarding local treatment of these metastases should be made following an MDT discussion (with a 100% consensus agreement among experts).

4.2.3. Diagnosis and treatment of patients in stage IIIb₃

For patients in Child-Pugh class B (>7 points) with extrahepatic metastasis, considering the selective use of modern TCM preparations indicated for liver cancer or treatments based on TCM with syndrome differentiation is recommended (evidence level 2, recommendation A). In China, TCM has long been used for HCC prevention and is viewed as an effective preventative treatment because of its HBV/HCV-suppressing effect.94, 95, 96, 97, 98 The research status of anti-HCC mechanisms in TCM revealed herbs have many active components that make them effective.⁹⁹ Many herbal formulas and their active ingredients are effective at inhibiting cell proliferation and inducing cell senescence, inducing apoptosis and autophagy, inhibiting metastasis and angiogenesis, improving drug resistance, and regulating immune function.¹⁰⁰ Additionally, the best supportive and palliative treatment (evidence level 2, recommendation A),101, 102, 103 including active analgesia, correction of hypoalbuminemia, nutritional support, blood glucose control in patients with diabetes, and addressing complications such as ascites, jaundice, hepatic encephalopathy, gastrointestinal bleeding, and hepatorenal syndrome, are recommended. For patients with symptomatic bone metastases, denosumab, bisphosphonates, or radionuclide therapy (strontium chloride) can be used to improve quality of life, alleviate suffering, and prolong survival.104, 105, 106

Recommendation 14: For patients with Child-Pugh class B (>7 points) with extrahepatic metastasis, restoring liver function to Child-Pugh B7 before the anti-tumor treatment is recommended. During the period, systemic anti-tumor drugs and other treatments can be selected after MDT discussion (with a 100% consensus agreement among experts).

4.3. Antiviral management for patients with virus-associated advanced liver cancer

Hepatitis virus infection is a significant risk factor in the development and progression of liver cancer. The effective inhibition of hepatic viruses is crucial in slowing down tumor progression and thus prolonging patient survival.^107,108 In China, 84% of liver cancers are attributed to HBV infection.¹⁰⁹ Long-term antiviral therapy effectively manages viral replication; however, the current antiviral drugs do not completely eliminate covalently closed circular DNA in patients with chronic HBV infection.¹¹⁰ Even patients who achieved serum clearance of hepatitis B surface antigen (HBsAg) may still have hidden HBV infection (i.e., patients with HBV DNA below the detection threshold following antiviral therapy). Such inapparent infections still carry the risk of HBV reactivation during anti-tumor treatment, often leading to the interruption of anti-tumor treatment due to complications, including hepatitis. HBV reactivation has been associated with malignant tumor progression and may affect anti-tumor efficacy.¹¹¹ Therefore, antiviral therapy is recommended for patients with HBV-related liver cancer who are HBsAg-positive, regardless of HBV DNA levels. Moreover, potent, low-resistance drugs such as entecavir, tenofovir disoproxil, and tenofovir alafenamide should be chosen based on the patient's condition of the patient during anti-tumor therapy (evidence level 1, recommendation A).^108,112 For HCV-related liver cancer, although the current anti-HCV regimen may cure HCV, HCV RNA reactivation can still occur during anti-tumor therapy.¹¹³ Therefore, patients with HCV-related liver cancer should increase the frequency of HCV RNA detection during anti-tumor treatment, and antiviral therapy should be timely administered once HCV RNA is positive (evidence level 1, recommendation A).¹¹⁴

Recommendation 15: Patients with HBV/HCV-related liver cancer and positive HBsAg/HCV RNA should promptly begin antiviral therapy (with a 100% consensus agreement among experts).

Recommendation 16: Patients with HBV and HCV-related liver cancer receiving anti-tumor therapy are at risk of viral reactivation. HBV DNA, HCV RNA, and liver function status should be closely monitored during treatment and antiviral treatment strategies adjusted in time (with a 100% consensus agreement among experts).

4.4. Systemic treatment and management of advanced liver cancer complicated with portal hypertension

The impact of portal hypertension should be considered when choosing systemic treatment for patients with advanced liver cancer complicated with portal hypertension. Treatment options that simultaneously reduce portal hypertension while avoiding those that exacerbate varicose veins or portal hypertension should be preferred. Clinical trials involving atezolizumab combined with bevacizumab and sintilimab combined with bevacizumab excluded patients at risk of bleeding from esophageal or gastric varices due to portal hypertension.^75,115,116 Further confirmation is needed to establish the safety of these treatments for liver cancer with portal hypertension. In addition, clinical studies have demonstrated that sorafenib and regorafenib can help reduce portal venous pressure, making them safe and effective treatment options for patients with severe portal hypertension.^15,117

Recommendation 17: Both liver cancer treatment and portal hypertension management should be established for patients with portal hypertension and liver cancer. The treatment regimen containing bevacizumab should be carefully considered in choosing a systemic treatment plan for patients with severe portal hypertension, particularly those with severe esophagogastric varices with red color signs. Other targeted drugs can be considered as alternatives, with close monitoring by doctors (with a 95% consensus agreement among experts).

5. Summary and future perspectives

Liver cancer in China exhibits significant distinctions from Western countries in terms of etiology, disease characteristics, disease progression, treatment modalities, and prognosis, leading to high heterogeneity. This consensus is established based on the Chinese liver cancer staging system and introduces a more nuanced staging approach, specifically focusing on advanced liver cancer stages IIIa and IIIb. Drawing on insights from relevant domestic and foreign studies and utilizing multidisciplinary collaboration, the selection of the most suitable treatment for stage IIIa liver cancer should be individualized, considering the liver function, previous treatment options, and concurrent medical conditions. This involves judiciously recommending surgical resection, TACE/HAIC, radiotherapy, systemic therapy, and other local treatment modalities as part of a well-planned treatment combination. For stage IIIb liver cancer, adopting the definition of oligometastasis used for other tumors is recommended. The treatment approach involves systemic therapy as the cornerstone of the treatment course, complemented by concurrent utilization of appropriate local therapies, such as radiotherapy, TACE, HAIC, and ablation. In addition, this consensus introduces a novel aspect by emphasizing the need for vigilant monitoring of HBV DNA and HCV RNA during anti-tumor therapy to assess their potential effects on tumor prognosis. A thorough investigation of how different anti-tumor drugs/combination therapies affect portal hypertension and related complications is also advocated, providing optimal drug recommendations. As ongoing research at domestic and international levels advances, this consensus will be periodically updated to ensure its continued relevance and efficacy in diagnosing and treating patients with advanced liver cancer.

Authors’ contributions

Xiufeng Liu, Feng Xia, and Yue Chen contributed equally to this work. Xiufeng Liu, Feng Xia, Yue Chen, Huichuan Sun, Zhengqiang Yang, Bo Chen, Ming Zhao, Xinyu Bi, Tao Peng, and Zhiwen Luo contributed to draft writing. Xiufeng Liu, Feng Xia, Yue Chen, Zhiwen Luo, and Aizier Ainiwaer provided technical and material support. Fusheng Wang and Yinying Lu contributed to the conception and design. Other experts participated in consensus discussion and suggestions. All authors read and approved the final manuscript.

Declaration of competing interest

The authors declare that there is no conflicts of interest.

List of experts (arranged in alphabetical order by the last name)

Aizier Ainiwaer (Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China), Xinyu Bi (Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China), Dan Cao (Abdominal Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China), Bo Chen (Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China), Rongxin Chen (Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China), Yue Chen (Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China), Jiamin Cheng (Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China), Shuangsuo Dang (Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China), Jie Gao (Department of Hepatobiliary surgery, Peking University People's Hospital, Beijing, China), Yanhang Gao (Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China), Yufeng Gao (Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China), Xinlei Gong (Department of Medical Oncology, Bayi Hospital Affiliated to Nanjing Chinese Medical University, Nanjing, Jiangsu, China), Yabing Guo (State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China), Yarong Guo (Department of Oncology, The First Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China), Zhen Huang (Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China), Long Jin (Department of Interventional Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China), Haiyang Li (Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China), Jianjun Li (The First Affiliated Hospital of the Army Medical University, Chongqing, China), Junhe Li (Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China), Junyi Li (Department of Infectious Diseases, The Third People's Hospital of Kunming City, Yunnan, China), Ke Li (Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China), Qiu Li (Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China), Wei Li (No.2 People's Hospital of Fuyang City, Fuyang, Anhui, China), Wenhua Li (The Third People's Hospital of Taiyuan, Taiyuan, Shanxi, China), Zhiwei Li (Department of hepatobiliary surgery, Shenzhen Third People's Hospital, Shenzhen, Guangdong, China), Ying Liu (Henan Cancer Hospital & Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China), Xiufeng Liu (Department of Medical Oncology, Bayi Hospital Affiliated to Nanjing Chinese Medical University, Nanjing, Jiangsu, China), Jun Lu (Hepatology and Cancer Biotherapy Ward, Beijing Youan Hospital, Capital Medical University, Beijing, China), Shichun Lu (Faculty of Hepato-Pancreato-Biliary Surgery, Institute of Hepatobiliary Surgery, Key Laboratory of Digital Hepatobiliary Surgery, Chinese People's Liberation Army Medical School, Chinese People's Liberation Army General Hospital, Beijing, China), Yinying Lu (Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China), Wei Lu (Tianjin Medical University Cancer Institute & Hospital, Tianjin, China), Zhiwen Luo (Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China), Fanping Meng (Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China), Yuemin Nan (Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China), Qin Ning (Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China), Zuoxing Niu (Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China), Shifang Peng (Xiangya Hospital of Central-South University, Changsha, Hunan, China), Tao Peng (Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China), Xiujuan Qu (Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China), Jie Shen (Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, China), Tianqiang Song (Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China), Huichuan Sun (Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China), Jian Sun (State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China), Fusheng Wang (Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China), Shuai Wang (Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China), Weihu Wang (Department of Radiation Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China), Wentao Wang (Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China), Xin Wang (Department of Abdominal Oncology/Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China), Lai Wei (Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China), Jianbing Wu (Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China), Feng Xia (Department of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China), Yong Xia (Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital and the National Center for Liver Cancer, The Second Military Medical University, Shanghai, China), Qing Xie (Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China), Long Xu (Department of Gastroenterology and Hepatology, Shenzhen University General Hospital, Shenzhen, Guangdong, China), Yongfeng Yang (The Second Hospital of Nanjing, Teaching Hospital of Southeast University, Nanjing, Jiangsu, China), Zhengqiang Yang (Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China), Jieer Ying (Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China), Chaohui Yu (Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China), Hongjiang Yu (Inner Mongolia Tongliao City Hospital, Tongliao, Inner Mongolia, China), Lingxiang Yu (Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China), Zhengang Yuan (Department of Oncology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China), Shan Zeng (Department of Oncology, Xiangya Hospital of Central-South University, Changsha, Hunan, China), Jing Zhang (The Third Unit, Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China), Jingdong Zhang (Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China), Lan Zhang (Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China), Haitao Zhao (Department of Liver Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China), Hong Zhao (Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China), Ming Zhao (Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China), Shi Zuo (Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China).