Chinese Expert Consensus on the Combination of Targeted Therapy and Immunotherapy with Locoregional Therapy for Intermediate/Advanced Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of China’s largest health threats. It is the fourth commonest cancer and the second leading cause of death in China among malignant tumors. Resection remains the best treatment option for patients with HCC to achieve long-term survival; however, only 15–30% of Chinese patients are considered eligible for hepatectomy since most of them are already in the intermediate or advanced stage at diagnosis and are only recommended for nonsurgical treatments, with a 5-year survival rate of only 14.1%.

Due to unsatisfactory results from conventional therapies, e.g., transcatheter arterial chemoembolization (TACE) and chemoradiotherapy, in patients with unresectable intermediate/advanced HCC, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led systemic treatment of HCC into a new era in recent years. Targeted therapy combined with immunotherapy has become the preferred systemic treatment option for patients with intermediate/advanced HCC, with continuously improved objective response rate (ORR). The median survival of patients administered targeted therapy combined with immunotherapy has increased from 10 months after sorafenib treatment to more than 20 months. Some patients with initially unresectable HCC achieve downstaging and conversion to undergo radical resection after systemic treatment, with long-term survival similar to that of patients initially resectable HCC.

A key to improve the conversion rate and prolong survival in patients with intermediate/advanced HCC is to explore therapeutic regimens conferring a high ORR by combining different treatment options. Targeted therapy combined with immunotherapy increases the ORR from less than 20% with monotherapy to 20–30%, while targeted therapy combined with immunotherapy and locoregional therapy, e.g., TACE, hepatic artery infusion chemotherapy (HAIC) and radiotherapy, may further increase the ORR to more than 60% and also convert 50% of intermediate/advanced HCC cases to curative resection. Targeted therapy combined with immunotherapy and locoregional therapy appeared to be effective in initial studies, but high-level evidence is still lacking. In addition, there is no consensus on the optimal combination of different treatment modalities, suitable patient groups, timing and sequence of combination, management of adverse reactions, etc. The regimens and experiences of different medical institutions vary greatly, resulting in uneven treatment levels. To further standardize the clinical practice of targeted therapy combined with immunotherapy and locoregional therapy for intermediate/advanced HCC, the Hepatic Oncology Branch and Immunology Branch of the China International Exchange and Promotive Association for Medical and Health Care invited well-known experts in the HCC field in China to examine the existing evidence and build a consensus to address the status quo of HCC diagnosis and treatment in China. It is further pointed out that the consensus was formulated based on the medical environment of HCC treatment in China, there is high incidence and heavy burden of HCC, with a great need to further improve the efficacy, combination therapy has been gradually applied in clinical practice, but there is a lack of broad consensus. This consensus aims to clarify the status and future challenges in combining targeted drugs, immune drugs and locoregional therapy for intermediate/advanced HCC, to summarize the current clinical results and to recommend the best practice of targeted therapy combined with immunotherapy and locoregional therapy, to help clinicians make better decisions for complex HCC cases, thereby improving therapeutic effects and the quality of life. In addition, this consensus is expected to promote innovations in clinical trials of HCC in China, promoting the application of targeted therapy combined with immunotherapy and locoregional therapy for HCC, increasing the overall level of HCC treatment in China, and improving therapeutic effects and patient survival in HCC. 15 consensus points (Table 1) are formulated in the applicable population and management, local treatment selection, conversion strategy, treatment strategy after tumor progression and management of adverse reactions finally.

This consensus refers to the “Guidelines for Diagnosis and Treatment of Hepatocellular Carcinoma (2022)” issued by the National Health Commission of China, adopts the Grading of Recommendations, Assessment, Development and Evaluation (GRADE), as well as the 2011 Oxford OCEBM Levels of Evidence as auxiliary tools to implement evidence grading, which is divided into five levels of evidence (1–5) and three levels of recommendation (strong recommendation [A], moderate recommendation [B], and weak recommendation [C]).

Consensus point 1: Definition of targeted therapy combined with immunotherapy and locoregional therapy for HCC.

Targeted therapy combined with immunotherapy and locoregional therapy refers to a comprehensive treatment that combines targeted drugs such as multi-target tyrosine kinase inhibitors (TKIs) or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies with ICIs and locoregional therapies such as surgical intervention and radiotherapy to improve the response rate in intermediate/advanced HCC (level of evidence: 2; strength of recommendation: A).

Significant progress has been made in HCC treatment with multi-target TKIs or anti-VEGF monoclonal antibodies combined with ICIs. The benefits of targeted therapy combined with immunotherapy for systemic treatment of HCC have been confirmed by multiple phase III randomized controlled trials, and this combination is recommended as a standard first-line therapy for HCC in the “Guidelines for Diagnosis and Treatment of Hepatocellular Carcinoma (2022).” Multiple global multi-center phase III studies have shown that atezolizumab combined with bevacizumab [1], sintilimab combined with a bevacizumab analog [2], or camrelizumab combined with apatinib [3] can significantly reduce mortality and disease progression compared with sorafenib monotherapy, with an ORR of about 30% (IMBrave150: 27.3% [RECIST 1.1], 33.2% [mRECIST]; ORIENT32: 21% [RECIST 1.1], 24% [mRECIST]; SHR-1210-III-310: 25.4% [RECIST 1.1], 33.1% [mRECIST]). Compared with single-target ICIs, cadonilimab (the world’s first dual-target ICI launched in June 2022, a progressive disease (PD)-1/CTLA-4 bi-specific antibody) combined with lenvatinib seemed to further increase the ORR (AK104-206: 44.4% [RECIST 1.1]), which needs further confirmation in phase III studies.

Targeted therapy combined with immunotherapy and locoregional therapy is a comprehensive treatment that combines targeted drugs such as multi-target TKIs or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies with ICIs and locoregional therapies such as surgical intervention and radiotherapy to improve the response rate of intermediate/advanced HCC. Tumor angiogenesis inhibitors are mainly divided into two categories, including multi-target TKIs (e.g., donafenib, lenvatinib, sorafenib, and apatinib) and anti-VEGF monoclonal antibodies such as bevacizumab and bevacizumab biosimilars. ICIs that block the PD-1/PD-L1 pathway include nivolumab, pembrolizumab, atezolizumab, sintilimab, camrelizumab, tislelizumab, and toripalimab. Locoregional therapies comprise TACE, HAIC, radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation (Cryo-A), intensity-modulated radiation therapy, stereotactic body radiation therapy (SBRT), Cyberknife, yttrium-90, etc.

Retrospective and prospective studies with small sample sizes have confirmed that patients with intermediate/advanced HCC benefit from targeted therapy combined with immunotherapy and locoregional therapy. Zhu et al. [4] performed a nationwide multi-center, retrospective cohort study in China, which included 456 patients with intermediate/advanced HCC based on propensity score matching. In this study, the subjects were divided into the test (targeted therapy combined with immunotherapy and TACE) and control (TACE alone) groups, which had ORRs of 60.1% and 32.0%, respectively; median progression-free survival (PFS) was longer in the test group than in the control group (9.5 months vs. 8.0 months; adjusted HR: 0.70, p = 0.002), and median overall survival (OS) was also significantly increased in the test group compared with the control group (19.2 months vs. 15.7 months; adjusted HR: 0.63, p = 0.001). For patients with intermediate/advanced HCC who were initially unresectable or refused to undergo resection, tolerable targeted therapy combined with immunotherapy and locoregional therapy can be selected upon comprehensive evaluation of the disease characteristics and organ functions to achieve greater benefits.

Consensus point 2: Patients with Ib, IIa, IIb, or IIIa HCC based on the China liver cancer [CNLC] stage system (shown inFig. 1) who are initially unresectable or refuse to undergo resection can receive targeted therapy combined with immunotherapy in addition to locoregional therapies. Those with CNLC stage IIIb HCC (with extrahepatic metastasis), whose tumor burden involves the liver, or with oligometastasis*/extensive metastasis can receive locoregional therapies in addition to targeted therapy combined with immunotherapy to relieve symptoms, improve the quality of life, maintain organ functions, or eliminate life-threatening factors, etc. (level of evidence: 2; strength of recommendation: A).

*Oligometastasis: number of metastatic sites ≤2, total number of metastases ≤5, and metastatic sites mainly in visceral organs such as liver, lungs, lymph nodes, and ovaries (Refer to the definition of oligometastasis in colorectal liver metastasis).

Consensus point 3: The timing of targeted therapy combined with immunotherapy and locoregional therapy should be determined on the basis of a comprehensive evaluation of tumor staging and the patient's general condition and organ functions, as well as multidisciplinary team (MDT) discussions. The treatment plan and cycle should be dynamically adjusted based on dynamic contrast-enhanced CT (DCE-CT) or dynamic contrast-enhanced MRI (DCE-MRI) conducted every 6–8 weeks, as well as serological tumor markers, blood biochemistry, and other indicators. It is recommended that patients administered effective conversion therapy undergo radical resection in a timely manner (level of evidence: 2; strength of recommendation: A).

Patients with CNLC stage Ib, IIa, IIb, or IIIa HCC who are initially unresectable or refuse to undergo resection can receive targeted therapy combined with immunotherapy in addition to locoregional therapies. Those with CNLC stage IIIb HCC (with extrahepatic metastasis), whose tumor burden involves the liver, or with oligometastasis*/extensive metastasis can receive locoregional therapies in addition to targeted therapy combined with immunotherapy.

The timing of targeted therapy combined with immunotherapy and locoregional therapy should be determined on the basis of comprehensive evaluation of tumor staging and the patient’s general condition and organ functions, as well as multidisciplinary team (MDT) discussions. The treatment plan and cycle should be dynamically adjusted based on dynamic contrast-enhanced CT (DCE-CT) or dynamic contrast-enhanced MRI (DCE-MRI) conducted every 6–8 weeks, as well as serological tumor markers such as AFP and PIVKA-II. Additionally, bone ECT scan, brain MRI or PET scan should be performed as appropriate to comprehensively assess tumor progression.

Multiple studies [5‒9] reported ORRs and disease control rates (DCRs) for targeted therapy combined with immunotherapy and locoregional therapy as the first-line regimen of 60–80% and 80–90%, respectively, in patients with advanced HCC. The regimen can rapidly shrink tumors, thereby improving the success rate of conversion therapy and prolonging survival (see online suppl. Material 1 for details; for all online suppl. material, see https://doi.org/10.1159/000540857).

There are no uniform recommendations regarding targeted therapy combined with immunotherapy and locoregional therapy for HCC. According to the “Guidelines for Diagnosis and Treatment of Hepatocellular Carcinoma (2022),” in clinical practice, angiogenesis inhibitors (multi-target TKIs or anti-VEGF monoclonal antibodies) + ICIs are most commonly used as a systemic treatment regimen. TACE, HAIC, local ablation (RFA, MWA, Cryo-A), and/or radiotherapy (intensity-modulated radiation therapy, SBRT, Cyberknife, yttrium-90) are further combined based on HCC staging, the patient's general condition and economic conditions, etc.

Consensus point 4: Targeted therapy combined with immunotherapy and TACE is recommended as the initial treatment option for patients with CNLC stage IIIa-IIIb HCC with initially unresectable tumors. Targeted therapy combined with immunotherapy can be combined in patients with CNLC stages Ib-IIb HCC that are initially unresectable and whose tumors continue to progress after 2–3 cycles of TACE treatment[10, 11] (level of evidence: 3; strength of recommendation: B).

TACE is the most widely applied locoregional therapy for HCC. Under the CNLC specifications and the guidelines issued by the Chinese Society of Clinical Oncology (CSCO), TACE can be used as a monotherapy or combined option for patients with CNLC stage Ib-IIIb HCC. New case-series studies have demonstrated that TACE, as a standard treatment for intermediate HCC, achieves a survival of 20–37 months and a median survival of 30 months [12‒15]. However, HCC exhibits a remarkable degree of heterogeneity, and TACE-resistant or TACE-refractory (no satisfactory results achieved after two cycles of TACE treatment) cases have been reported. It is therefore generally accepted in clinical practice that, if tumor growth cannot be controlled after 2–3 cycles of TACE treatment, the regimen should be adjusted or combined with systemic treatment or other locoregional therapies, including ablation, radiotherapy, etc. [10, 11]^.For advanced HCC (CNLC stages IIIa and IIIb), TACE should be initially combined with systemic treatment [16]. As targeted therapy and immunotherapy have become first-line options for systemic treatment of HCC, targeted therapy combined with immunotherapy and TACE is increasingly used in clinical practice [17‒22] (see online suppl. Material 2 for details).

To sum up, targeted therapy combined with immunotherapy and TACE or TACE combined with immunotherapy is providing a new era of exploration and development in patients with refractory intermediate/advanced HCC in case of sufficient liver function and performance status to tolerate the treatment. However, there is no consensus on the selection of targeted therapy combined with immunotherapy or immune drugs in combination with TACE, as well as the timing and sequence of combination with TACE, which needs to be clarified in further clinical trials.

Consensus point 5: Targeted therapy combined with immunotherapy and HAIC can be considered for CNLC stage IIb HCC patients with high tumor burden and ill-defined boundaries, CNLC stage IIIa HCC patients with portal vein tumor thrombus (PVTT) (especially Vp3, Vp4) and/or hepatic vein tumor thrombus (HVTT), or CNLC stage IIIb HCC patients with tumors mostly confined to the liver. Targeted therapy combined with immunotherapy and HAIC is also recommended as salvage therapy for patients with advanced HCC who experience disease progression after first-line targeted therapy combined with immunotherapy or first-line targeted therapy and for those with disease progression after first-line TACE (level of evidence: 3; strength of recommendation: B).

It is recommended to perform HAIC using the modified implantation method of port-catheter system or pure puncture plus catheter implantation. Intrahepatic and extrahepatic blood flow redistribution needs to be completed during the operation to protect the gastrointestinal mucosa and ensure proper drug delivery to all liver tumors. It is recommended to administer oxaliplatin and 5-fluorouracil by continuous intravenous infusion for 48–72 h, once every 3–4 weeks for 4–6 cycles, or until tumor progression. The number of treatment cycles and dosage should be adjusted timely according to adverse reactions [23].

Two randomized controlled clinical trials confirmed the efficacy of a targeted drug combined with HAIC for advanced HCC with PVTT. In these studies, sorafenib combined with HAIC achieved significantly prolonged survival compared with sorafenib monotherapy (Zheng et al. [24], median OS: 16.3 months vs. 6.5 months; He et al. [25], median OS: 13.37 months vs. 7.13 months). Lai et al. [26] performed a prospective, single-center clinical study of 36 patients with unresectable intermediate/advanced HCC who received lenvatinib combined with toripalimab and FOLFOX-HAIC, with ORR, DCR and median PFS of 66.7% (mRECIST), 88.9%, 10.4 months, respectively. Zhang et al. [27] carried out a prospective clinical study of patients with unresectable intermediate/advanced HCC administered donafenib combined with sintilimab and FOLFOX-HAIC, in whom ORR, DCR, and median PFS were 78.3% (mRECIST), 95.7%, and 10.2 months, respectively.

Consensus point 6: Patients with CNLC stage IIa, IIb and IIIa HCC are eligible for radiotherapy targeting primary lesions and PVTT/HVTT, plus targeted therapy combined with immunotherapy. CNLC stage IIIb HCC patients with hilar hepatic and/or retroperitoneal lymph node metastases can benefit from radiotherapy targeting primary lesions, metastatic lymph nodes and lymphatic drainage region, plus targeted therapy combined with immunotherapy. CNLC stage IIIb patients with oligometastasis can be administered radical radiotherapy for metastases, plus targeted therapy combined with immunotherapy. For these patients, local radiotherapy can be performed within 3 months to improve the radical cure rate and prolong PFS in case of effective targeted therapy combined with immunotherapy (level of evidence: 3; strength of recommendation: B).

Consensus point 7: SBRT can be performed in 3, 5, 9, or 10 fractions according to the positional relationship between normal organs and tumors. It is recommended to perform conventionally fractionated radiotherapy with simultaneous integrated boost (GTV 50–60 Gy/20–25 fractions, PTV 40–50 Gy/20–25 fractions) in patients with sufficient future liver remnant, using a higher radiation dose per fraction or even a radical dose (level of evidence: 3; strength of recommendation: B).

Compared with sorafenib monotherapy, targeted therapy combined with immunotherapy significantly improves PFS and OS in patients with unresectable HCC. However, overall, the response rate of targeted therapy combined with immunotherapy is only 20–30%, with a median PFS of 4–6 months. HCC patients with tumor thrombus have worse outcomes. A subgroup analysis of the Imbrave 150 study demonstrated that atezolizumab combined with bevacizumab was not significantly superior to sorafenib monotherapy in terms of efficacy in HCC patients with Vp4 PVTT [28, 29]. Radiotherapy is far more effective for tumor thrombus of HCC than targeted therapy combined with immunotherapy, and exerts synergistic antitumor effects via a variety of mechanisms in combination with targeted therapy plus immunotherapy: (1) radiotherapy increases immune cell infiltration into tumors, but also induces the upregulation of immune checkpoint molecules (such as PD-1, PD-L1, and CTLA-4) and VEGF expression; (2) angiogenesis inhibitors promote the normalization of tumor vasculature to improve the efficacy of radiotherapy and further enhance cytotoxic T-cell infiltration into tumors, but also upregulate PD-1 expression by CD4⁺ T cells; (3) ICIs improve the efficacy of radiotherapy and angiogenesis inhibitors [30]; (4) ICIs significantly improve the abscopal effect of radiotherapy to enhance their own efficacy. Therefore, targeted therapy combined with immunotherapy and radiotherapy can potentially improve treatment efficacy in patients with unresectable HCC. Most clinical studies on targeted therapy combined with immunotherapy and radiotherapy are phase I trials or retrospective studies [31‒38] (see online suppl. Material 3 for details), while large prospective studies are lacking, and many problems remain to be solved, e.g., (1) whether the fractionation mode affects the combination therapy; (2) whether there are differences in the efficacy and adverse reactions between radiotherapy combined with targeted therapy and radiotherapy combined with immunotherapy; (3) whether the combination of radiotherapy, targeted therapy and immunotherapy can improve treatment efficacy.

In summary, previous studies and clinical observations have confirmed the safety of radiotherapy combined with targeted therapy or immunotherapy, but significantly increased adverse reactions for radiotherapy combined with targeted therapy and immunotherapy have been reported. Therefore, multiple factors should be considered when selecting a patient population for the triple therapy. On the one hand, efficacy should be considered. The triple therapy is preferred for patients with high-risk distant metastases or with lesions out of the radiotherapy field, ensuring treatment benefits. On the other hand, it is necessary to carefully assess the patient's condition to determine patient tolerance, and, if necessary, adjust the dose of the targeted drug.

Consensus point 8: Liver resection for HCC after conversion therapy of targeted therapy combined with immunotherapy and locoregional therapy requires a comprehensive assessment of the possible benefits and surgical tolerance. The maximum functional liver remnant volume should be preserved in liver resection, and safe margins should be ensured. Minimally invasive resection techniques, e.g., laparoscopic resection and robotic resection, can be performed in medical institutions where conditions permit (level of evidence: 2; strength of recommendation: C).

The low radical resection rate and high recurrence rate after surgery limit the improvement of patient survival in HCC, so conversion therapy emerged as an important tool to reduce recurrence and provide resection opportunities. Studies have shown a 5-year survival rate in patients who undergo resection after conversion therapy of 50–60% [39‒41]. In the “Guidelines for Diagnosis and Treatment of Hepatocellular Carcinoma (2022),” conversion therapy is listed as one of the main treatment options for unresectable HCC. At present, conversion therapy mainly uses a multidimensional combination and multi-modal sequence of PD-1 inhibitors combined with TKIs locoregional therapies, including TACE, HAIC, SBRT, portal vein embolization, and associating liver partition and portal vein ligation for staged resection] [42].

The indications of hepatectomy after conversion therapy in patients with unresectable HCC are the same as those of liver resection in patients with resectable HCC [43, 44], but hepatectomy after conversion therapy requires selecting appropriate timing. Considering that combination therapy may cause liver injury and drug resistance may be induced by long-term treatment in patients with HCC, most investigators believe that patients who cannot access surgery due to technical reasons should undergo resection as soon as possible after meeting the criteria for resectability [45]. Patients are evaluated after conversion therapy according to RECIST 1.1/mRECIST. It is recommended that patients who meet the following criteria undergo surgery as soon as possible: (1) efficacy evaluated as complete response (CR)/partial response (PR); (2) residual liver volume after surgery not less than 40% of the standard liver volume, which is necessary for maintaining normal liver function; (3) criteria for radical resection met; (4) no other surgical contraindications [46].

Hepatectomy after conversion therapy requires full consideration of the patient’s specific condition. On the one hand, conversion therapy of systemic treatment combined with locoregional therapy results in controlled tumor burden, reduced tumor volume, and inactivated and regressed tumor thrombus. On the other hand, however, multidimensional combination therapy may lead to impaired liver functional reserve, as well as reduced surgical tolerance and wound healing ability. These patients tend to have larger tumors, requiring a larger resection range and larger surgical incisions [47]. Under the premise of ensuring complete tumor resection (R0 resection) and safe margins, reducing surgical incisions and improving surgical safety are important issues for hepatectomy after conversion therapy.

The following principles should be considered for hepatectomy after conversion therapy: (1) the maximum functional liver remnant volume should be preserved in liver resection, ensuring safe margins instead of blindly pursuing extensive liver resection which may lead to massive loss of normal liver tissue [48‒50]; (2) patients that achieve deep remission after conversion therapy can benefit from “narrow margin” or even “zero margin” resection with significantly higher safety; (3) in patients undergoing hepatectomy after conversion therapy, liver injury caused by long-term combination therapy may lead to enhanced intraoperative hemorrhage and postoperative complications. Therefore, hepatectomy after conversion therapy should rely more on technical tools such as three-dimensional visualization, intraoperative ultrasound, fluorescence laparoscopy, and robot assistance than conventional liver resection to make the surgery more minimally invasive and precise, reduce surgical incisions, improve the precision of surgery, and accelerate postoperative recovery.

Minimally invasive surgical procedures (laparoscopic liver resection, robot-assisted laparoscopic liver resection, etc.) have good clinical value for HCC patients after conversion therapy. First, as mentioned above, HCC patients after conversion therapy show reduced surgical tolerance and decreased liver functional reserve, and experience more surgical complications (intraoperative hemorrhage, delayed wound healing, and postoperative bile leakage, etc.) than those administered conventional liver resection. Minimally invasive liver resection methods, e.g., laparoscopic liver resection and robot-assisted laparoscopic liver resection, may reduce surgical incisions and accelerate postoperative rehabilitation, with great clinical value in patients who are likely to achieve complete remission. Second, patients who undergo minimally invasive liver resection may resume targeted therapy combined with immunotherapy earlier, which may further improve prognosis [50‒52].

The ultimate goal of conversion therapy is not surgical resection but improved OS. Because of the high heterogeneity of HCC, it is necessary for patients undergoing hepatectomy after conversion therapy to resume adjuvant therapy after surgery. In HCC patients who undergo R0 resection after conversion therapy, it is generally recommended to adopt sequential targeted therapy combined with immunotherapy based on performance status, adverse reactions and surgical tolerance; in those surgically treated after conversion therapy with pathology showing complete tumor necrosis, the original regimen or some of the drugs included in the original regimen may be used as adjuvant therapy for more than 6 months. In case of no tumor recurrence or metastasis in two consecutive imaging examinations, with tumor markers in the normal ranges for 3 consecutive months, drug discontinuation may be considered [53].

Consensus point 9: In patients with tumor thrombus (if any) shrinking or even disappearing, tumors shrinking to ≤5 cm (≤3 tumors), and hepatic dysfunction rated as Child-Pugh class A/B upon targeted therapy combined with immunotherapy[54, 55], ablation therapy can be added (level of evidence: 1; strength of recommendation: A). Ablation therapy is generally performed at an interval of 1–2 weeks, which depends on liver function, performance status and treatment response.

Local ablation for HCC can be performed by the percutaneous, laparoscopic, or open approach. Ablation therapies include Cryo-A, thermal ablation (RFA and MWA), high-voltage pulse ablation (irreversible electroporation), and chemical ablation (percutaneous ethanol injection), etc. Among these methods, RFA and MWA are currently the most commonly used tools. Both methods have the advantages of easy operation, short hospital stay, definite curative effects, controllable ablation range, and low complication rate, which are especially suitable for patients with advanced age, comorbidities, severe cirrhosis, and tumors located deep in the liver or centrally located HCC [56‒64]. It was demonstrated clinically that Cryo-A and thermal ablation are comparable in terms of efficacy, but the risk of hemorrhage of Cryo-A is relatively higher [65]. As a beneficial supplement to Cryo-A and thermal ablation, irreversible electroporation can be used for HCC invading the intestinal canal, diaphragm, porta hepatis, etc., and may be performed without general anesthesia, indicating broad application prospects [66]. The physician can select the appropriate ablation method based on patient condition, lesion characteristics, experience, and ablation equipment accessibility.

Consensus point 10: In HCC patients with progressive disease (PD) after targeted therapy combined with immunotherapy and locoregional therapy, second-line systemic antitumor treatment can be performed as tolerated (Child-Pugh class ≤B7 or ECOG score ≤1) based on liver function and the patient’s general condition, while locoregional therapy is continued to control non-extensively progressive lesions under the guidance of a MDT (level of evidence: 4; strength of recommendation: B). Patients with poor liver function and general condition (Child-Pugh class ≥B8 or ECOG score ≥2) should be provided the best supportive care and traditional Chinese medicine (level of evidence: 2; strength of recommendation: A), followed by antitumor therapy after liver function improves.

In clinical practice, targeted therapy combined with immunotherapy and locoregional therapy is used in many patients with HCC to achieve the highest conversion rate and best clinical benefits. However, 45–80% of patients have no opportunity to undergo hepatectomy after conversion therapy due to differences in response, future liver remnant, and liver function, and subsequently show disease progression. The general condition and liver function should be firstly assessed in these patients. For cases with Child-Pugh class ≥B8, it is recommended to combine appropriate modern Chinese medicine preparations or TCM syndrome differentiation treatment [67‒73] based on the best supportive care [10, 74, 75]. Icaritin [76] is effective against tumors while improving the quality of life of patients. In patients with Child-Pugh class ≤B7, it is recommended to replace the systemic treatment regimen with regorafenib [77], pembrolizumab [78‒80], apatinib [81], ramucirumab [82] or other second-line treatment options. Meanwhile, appropriate locoregional therapies, e.g., intervention and radiotherapy, can be performed in combination with the existing treatment based on tumor progression and evaluation by an MDT to control locally progressive lesions.

Consensus point 11: In HCC patients with progression after remission (CR, PR) following targeted therapy combined with immunotherapy and locoregional therapy, while receiving targeted therapy combined with immunotherapy, the treatment strategy should the same as the above Consensus Point 10; in case they are in the stage of dose reduction or drug discontinuation, it is recommended to resume the original combination regimen or replace it with a second-line regimen. In patients with locally progressive and new lesions, locoregional therapy can be combined under the guidance of an MDT, and biopsy of new lesions can be performed when necessary (level of evidence: 4; strength of recommendation: B).

Patients achieving radiographic CR or pathological CR following targeted therapy combined with immunotherapy and locoregional therapy should receive reduced doses or discontinue the treatment. There are currently no clinical trials or guidelines recommending standard treatment approaches for cases progressing after remission (CR, PR) following targeted therapy combined with immunotherapy and locoregional therapy. It is recommended to resume the initial standard-dose targeted therapy combined with immunotherapy or replace it with a second-line regimen based on full communication with the patient. Moreover, it is recommended to perform locoregional therapies, including surgery, intervention and radiotherapy, for new lesions. If possible, aspiration biopsy of new lesions is recommended for definitive diagnosis of tumors and elimination of heterogeneous interference. For cases in remission after targeted therapy combined with immunotherapy and locoregional therapy but still receiving targeted therapy combined with immunotherapy, it is recommended to replace it with a second-line regimen and combine locoregional therapy based on MDT discussions.

Consensus point 12: Necessary baseline assessments and screening should be performed prior to targeted therapy combined with immunotherapy. In patients receiving immunotherapy, medical history inquiry and the management of underlying diseases should be routinely carried out, as well as full baseline testing, including routine blood test, liver function test, renal function test, thyroid function test, hypothalamic-pituitary axis evaluation, myocardial enzyme test, brain natriuretic peptide (BNP) test, urinalysis, ECG, and chest CT. A comprehensive assessment by an MDT is recommended for patients with definite underlying diseases based on medical history assessment. Immunotherapy should be initiated after adequate management of underlying diseases or comorbidities, and patients with HBV should be screened for baseline HBV DNA and administered conventional antiviral treatment (level of evidence: 2; strength of recommendation: A).

Consensus point 13: Side effects should be managed and monitored throughout targeted therapy combined with immunotherapy. Such symptoms as pyrexia, rash, myasthenia, diarrhea, dyspnea, chest tightness and palpitations, visual change, numbness of hands and feet, altered state of consciousness and edema of lower extremities should be monitored; blood pressure should be routinely monitored, and routine blood test, hepatic function test, renal function test, pancreatic function test, myocardial enzyme test, brain natriuretic peptide test, thyroid function test, ECG and chest CT should be carried out regularly (level of evidence: 2; strength of recommendation: A).

Consensus point 14: Key points for the diagnosis and treatment of the side effects of targeted therapy combined with immunotherapy: It is recommended to 1) determine the relationship and severity of side effects based on clinical manifestations, laboratory test results and toxicity of the drugs used; 2) decide the discontinuation of targeted drugs or ICIs and start treatment with glucocorticoids based on the relationship and severity of adverse events (AEs); 3) manage AEs of grades 3–4 based on the comprehensive assessment by an MDT (level of evidence: 2; strength of recommendation: A).

Consensus point 15: Management of the common AEs of targeted therapy combined with immunotherapy and locoregional therapy for HCC: The temporal relationship of AEs with the drugs and locoregional therapy should be noticed in case of AEs occurring during targeted therapy combined with immunotherapy and locoregional therapy, and symptomatic treatment should be primarily considered for any AE associated with locoregional therapy. In case of side effects from targeted therapy combined with immunotherapy, locoregional therapy should be resumed only after such side effects are reduced, and organ functions restored to be tolerable level (level of evidence: 2; strength of recommendation: A).

Small-molecule TKIs (such as donafenib, lenvatinib, sorafenib, and apatinib) and the anti-VEGF monoclonal antibody bevacizumab are the main drugs used in targeted therapy for HCC. The common side effects of targeted drugs include hypertension, proteinuria, rash, hand-and-foot syndrome, diarrhea, nausea, vomiting, abdominal distension, decreased appetite, hypothyroidism, hemorrhage and thrombopenia [83, 84].

ICIs generally activate immune responses while relieving the suppressed function of T cells and inducing immune response to tumors. After treatment witch ICIs, the excessively activated immune system may result in the loss of the body’s tolerance and induce errant nontumor self-directed immune responses, causing immune-related AEs (irAEs) [2, 56, 84‒86]. The spectrum of potential diseases associated with irAEs is very extensive. These diseases may involve all organs and systems, resulting in multiple clinical manifestations. The occurrence, occurrence site, occurrence time and severity of irAEs remain uncertain after immunotherapy in individual patients. irAEs show a very low incidence in a specific organ, and most of them are mild to moderate. Since the mechanism of inflammatory injury is definite, and irAEs are sensitive to hormones, the majority of irAEs can resolve upon treatment.

irAEs commonly occur in organs or systems such as the skin, endocrine system, gastrointestinal tract, liver, lungs, heart, blood system, nervous system, kidneys, muscle, joint, etc. The general principles for the management of irAEs encompass screening for risk factors prior to medication, baseline assessments, propaganda and education on irAEs; close monitoring of irAEs after medication; early diagnosis and treatment of irAEs; and reasonable use of hormones and/or immunosuppressants. The whole process of patient management should involve an MDT. The general grading principles and management recommendations are similar for the immunotherapy of tumors in different systems. Details are found in the Guidelines for Management of Immune Checkpoint Inhibitor Toxicities issued by the CSCO and NCCN Guidelines for Management of Immunotherapy-Related Toxicities [86‒90]. Side effects of locoregional therapies for HCC and their characteristics:

Locoregional therapies may induce side effects such as headache, pyrexia, local inflammatory response, infections, hemadostenosis, and vascular thrombosis, which show definite temporal relationships, and are mostly mild to moderate. The chemotherapeutic drugs used in HAIC may induce side effects. For example, oxaliplatin may cause moderate bone marrow suppression, moderate emetic effects, neurotoxicity, and anaphylaxis (dose-accumulating toxicity, most occurring after 5–6 treatment cycles). Side effects observed with 5-fluorouracil include moderate bone marrow suppression, moderate emetic effects, occasional oral mucositis and diarrhea, occasional neurotoxicity, and occasional cardiovascular adverse reactions. Hepatic and renal toxicities associated with the abovementioned drugs are mild.

Post-ablation syndrome may occur following RFA, with symptoms including pyrexia, pain, consumptive symptoms, infections (liver abscess), hemorrhage (gastrointestinal or intraperitoneal hemorrhage), hepatic insufficiency, hepatic failure, and injury of adjacent organs (gallbladder, stomach and intestine, bile duct, diaphragm, etc.) The side effects of radiotherapy for HCC include bone marrow suppression (low white blood cell and platelet counts), hepatic injury (radiation hepatitis, etc.), bone damage (e.g., osteoporosis), decreased immunity, skin and muscle injuries, gastrointestinal reactions (pernicious vomiting and anorexia), etc.

As irAEs are primarily inflammatory diseases, a specific irAE occurs with the inflammatory injury of a certain organ as the pathophysiological basis, and most irAEs have definite clinical manifestations, including ICI-related pneumonitis and rash, which are easy to differentially diagnose clinically. However, irAEs and targeted drugs may have common side effects of organ injuries. With respect to treatment, irAEs of more than grade 2 require treatment with immunosuppressants, including glucocorticoids (except endocrine system toxicities), while the side effects of targeted drugs primarily require symptomatic management, treatment discontinuation in severe cases but generally no hormone therapy. Therefore, when there are side effects related to both targeted drugs and ICIs in targeted therapy combined with immunotherapy, the relationship and accurate grades of AEs should be determined as much as possible, followed by relevant treatment.

The spectrum of side effects induced by the targeted drugs used in targeted therapy combined with immunotherapy is relatively narrow, while the irAEs of ICIs are various and show a wide spectrum. Clinical diagnosis and treatment led by an MDT is recommended for other clinical manifestations or abnormal laboratory findings during targeted therapy combined with immunotherapy. The characteristics of AEs that may occur during targeted therapy combined with immunotherapy and require differential diagnoses are shown in online supplementary material 4, as well as key points for treatment.

Adverse reactions including pyrexia, headache, hemorrhage, nausea, vomiting, and abnormal routine blood test results following targeted therapy combined with immunotherapy and locoregional therapy are mostly definitely diagnosed based on their temporal relationship with the locoregional therapy and manifestations. Adverse reactions that may occur during targeted therapy combined with immunotherapy and locoregional therapy and require differential diagnoses include hepatic injury, pyrexia, thrombocytopenia, etc. Online supplementary material 5 presents their clinical characteristics and key points for treatment.

Targeted therapy combined with immunotherapy, and targeted therapy combined with immunotherapy and locoregional therapy have been hot topics in the treatment of intermediate/advanced HCC in recent years. ICI-based combination regimens have shown significantly improved therapeutic effects in intermediate/advanced HCC. However, with the popularization of targeted therapy combined with immunotherapy and locoregional therapy, how to identify patients who can benefit from immunotherapy, which combination therapy to apply, the timing of combination and how to effectively prevent and control adverse reactions induced by such combination urgently need to be resolved. This consensus was based on existing clinical data and expertise, and will be adjusted with the continuous maturation and refinement of data. Therefore, prospective multi-center, large sample, controlled studies with the combination of targeted therapy and immunotherapy with locoregional therapy are encouraged, especially the studies showing long-term survival outcomes. The locoregional therapy can be single, such as TACE, HAIC, radiotherapy, etc., or it can be a combination of different locoregional treatment modalities for special populations, such as TACE-HAIC, TACE-radiotherapy, TACE combined with intraoperative ablation, etc. It is also encouraging that many novel ICI-based combination regimens are currently under clinical investigation, e.g., anti-CTLA-4 monoclonal antibody, anti-LAG-3 monoclonal antibody, anti-TIGIT monoclonal antibody, anti-PD-1/CTLA-4 bispecific antibody and anti-PD-1/VEGF bispecific antibody, besides the anti-PD-(L)1 antibody. The domestic cadonilimab (anti-PD-1/CTLA-4 bispecific antibody) has been marketed, and ivonescimab (anti-PD-1/VEGF bispecific antibody), another bispecific antibody as a targeted therapy combined with immunotherapy will also be marketed soon. With more novel drugs investigated in clinical trials and continuous research advances, the immunotherapy-based combination strategy can not only further improve the therapeutic effects in intermediate/advanced HCC, but also provide additional conversion opportunities for patients with unresectable HCC. Though the relationship between ORR and OS remains controversial, quality-of-life-based OS as the ultimate goal of HCC treatment is widely recognized. In HCC treatment, deep multidisciplinary cooperation should be engaged, and individualized treatment regimens should be established based on the specific condition of each HCC patient to gradually achieve precise treatment of HCC.

The authors have no conflicts of interest to declare.

This research was funded by Chinese Academy of Medical Sciences Medical and Health Technology Innovation Fund, CAMS Innovation Fund for Medical Sciences (CIFMS) (no.2021-I2M-1-066, 2021-I2M-C&T-B-043) and Beijing Xisike Clinical Oncology Research Foundation Y-XD202001-0111. The funding organizations had no role in study design or concept; collection, management, analysis, or interpretation of data; or preparation, review, or approval of manuscript.

Xinyu Bi, Yinying Lu, Bo Chen, Zhengqiang Yang, Zhixian Hong, and Hanping Wang contributed equally to the work and were responsible for the investigation, data curation, and writing – original draft. Jianqiang Cai, Haitao Zhao, and Hong Zhao contributed to conceptualization, methodology, writing – review and editing, supervision. Yongkun Sun, Xiaodong Wang, Chunwang Yuan, and Daobing Zeng contributed to writing – original draft, material support. Zhen Huang, Aiping Zhou, Wen Zhang, Shunda Du, Jianjun Zhao, Jianguo Zhou, Yirui Zhai, and Xu Che were responsible for data curation and material support. All authors read and approved the final manuscript.

Xinyu Bi, Yinying Lu, Bo Chen, Zhengqiang Yang, Zhixian Hong, and Hanping Wang contributed equally to this work.