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Systemic Therapy for Hepatocellular Carcinoma: Chinese Consensus-Based Interdisciplinary Expert Statements

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer and causes many cancer-related deaths worldwide; in China, it is the second most prevalent cause of cancer deaths. Most patients are diagnosed clinically with advanced stage disease. Summary: For more than a decade, sorafenib, a small-molecular-weight tyrosine kinase inhibitor (SMW-TKI) was the only molecular targeted drug available with a survival benefit for the treatment of advanced HCC. With the development of novel TKIs and immune checkpoint inhibitors for advanced HCC, the management of patients has been greatly improved. However, though angiogenic-based targeted therapy remains the backbone for the systemic treatment of HCC, to date, no Chinese guidelines for novel molecular targeted therapies to treat advanced HCC have been established. Our interdisciplinary panel on the treatment of advanced HCC comprising hepatologists, hepatobiliary surgeons, oncologists, radiologists, pathologists, orthopedic surgeons, traditional Chinese medicine physicians, and interventional radiologists has reviewed the literature in order to develop updated treatment regimens. Key Messages: Panel consensus statements for the appropriate use of new molecular -targeted drugs including doses, combination therapies, adverse reaction management as well as efficacy evaluation, and predictions for treatment of advanced HCC with evidence levels based on published data are presented, thereby providing an overview of molecular targeted therapies for healthcare professionals.


Introduction
Globally, hepatocellular carcinoma (HCC) is one of the main causes of cancer-related mortality. In 2015, morbidity and mortality in China were 370,000 and 326,000 people, respectively [1]. HCC is clinically characterized by an unperceived onset, rapid progression, early DOI  recurrence, and late-stage diagnosis and is difficult to treat, resulting in a poor prognosis.
In recent years, significant advances have been made in the development of molecular targeted drugs for HCC therapy [2]. In 2007, the FDA in the USA approved tyrosine kinase inhibitors (TKIs) sorafenib for the therapy of advanced HCC. Subsequently, worldwide approval was given for the use of several other oral multi-targeted TKIs to treat HCC. In China, the development of molecular targeted therapies for advanced HCC began in 2006. Data from the Asia-Pacific ORIENTAL trial that compared sorafenib versus placebo were given in 2008 at the American Society of Clinical Oncology, which finally lead to its approval in the same year. Thereafter, more than 160,000 patients have been treated in China with sorafenib being the gold standard for those diagnosed with advanced stage disease.
The new multi-targeted TKIs, regorafenib, lenvatinib, and donafenib, which became available in China after 2017, have expanded the options for the treatment of advanced HCC and provided effective therapy for recurrent/progressive disease. Additionally, apatinib is a novel molecular targeted drug for HCC treatment and has been provided by Chinese companies in recent years [3]. Anlotinib has been proven to be effective also for HCC, though it is still under investigation in phase 2 clinical trials. Also, ramucirumab and cabozantinib are, in China, still under investigation after they were approved by the FDA for HCC treatments 2 years before, but they can serve as indicators for HCC treatments in China within the next years. Other molecular targeted therapies include programmed cell death protein (PD-1) inhibitors as mono-or combination therapies (Table 1). In the era of immunotherapy, molecular targeted therapy and immunotherapy are both novel therapies for HCC and mo-lecular targeted therapy combined with immunotherapy as systemic treatment has become a new approach for advanced HCC. However, the CKECKMATE-459 [4] and KEYNOTE240 [5] studies revealed that molecular targeted therapy is still the major cornerstone treatment for advanced HCC. We took targeted therapy as the entry point to guide the application selection of targeted therapy drugs in different scenarios, while a consensus on the application of immunotherapy will be introduced in the future.
How to select the currently available molecular targeted drugs under various disease status and how to combine them with other drugs is one of the remaining critical issues in treating advanced HCC. The interdisciplinary expert panel consensus statements are based on the clinical symptoms of HCC in China, clinical trial outcomes, experience with current molecular targeted therapies regarding adverse events (AEs), drug dose selection, efficacy evaluation, efficacy predictions, and multidisciplinary collaboration treatment experiences. The aim of our expert panel statements was to guide physicians, patient's advocates, healthcare providers, and medical institutions in the appropriate application of molecular targeted therapies for advanced HCC.

Methods
The levels of clinical evidence and the strength of statements given by the expert panel are applied strictly to Chinese practice. Consensus was oriented based on the European Society for Medical Oncology guiding principles for HCC published in 2018 [6] and the Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma of the Chinese Society of Clinical Oncology published in 2020. Five levels of evidence were graded according to the therapeutic studies and four degrees of statement implemented and classified (Tables 2, 3). Molecular targeted therapy is defined as a drug which interferes with specific targeted molecules and is differentiated from hormonal or chemotherapies.

Single Molecular Targeted Monotherapies
First-Line TKI Medications The SHARP research [7] and the Asia-Pacific study [8] proved sorafenib to have good efficacy and well tolerated as first-line therapy for patients with advanced stage HCC disease. The SHARP study enrolled 602 patients. The median overall survival (OS) time for sorafenib was 10.7 months compared to 7.9 months for the placebo (HR = 0.69). The median time to progression (TTP) was 2.8 months for the placebo and 5.5 months for sorafenib. The ORIENTAL study enrolled 271 patients randomized at a 2:1 ratio to be given sorafenib or a placebo. The median OS time was 6.5 and 4.2 months (HR = 0.68), and the median TTP 2.8 and 1.4 months, respectively. Despite differences between ethnicities of the enrolled populations in the two studies, sorafenib produced basically the same OS time benefit.
The REFLECT study enrolled 954 medically untreated patients with advanced HCC who were randomly allocated to either lenvatinib or sorafenib therapy. The median OS times in the two groups were 13.6 and 12.3 months, respectively, with the data showing that lenvatinib was not inferior to sorafenib (HR = 0.92, 95% CI: 0.79-1.06), a finding consistent with the primary endpoint. Progression-free survival (PFS) in the two groups was 7.4 and 3.7 months, respectively (p < 0.000, HR = 0.66, 95% CI: 0.57-0.77). Analyzing separately the subgroups for lenvatinib and sorafenib for mainland China, Taiwan, and Hong Kong, 144 patients were involved. The OS times were 15.0 and 10.2 months, and the PFS times were 9.2 and 3.6 months, respectively. In this study, the rates of treatment-emergent AEs ≥3 were similar in both groups (episodes per patient-year 3.2 in the lenvatinib group vs. 3.3 in the sorafenib group). The most common treatment-related AEs (TRAEs) were slightly different. Hypertension and decreased appetite occurred more frequently in those patients treated with lenvatinib, yet palmar-plantar erythrodysesthesia was more common in the sorafenib group [9].
The ZGDH3 study [10] involved 668 randomized patients who received donafenib or sorafenib. The main endpoint was OS, and the median OS in the two groups was 12.1 and 10.3 months, respectively (p = 0.036). Secondary endpoints were PFS and response rates, which were 3.7 and 3.6 months (p = 0.282), and response rates 4.6% and 2.7% (p = 0.245), respectively. The rate of TRAEs of grade ≥3 was 57.4% and 67.5% (p = 0.008), respectively. Compared with sorafenib, donafenib produced prolonged survival and caused fewer TRAEs.
Another first-line phase 2 study of advanced HCC enrolled 121 patients to receive apatinib 750 mg qd or 850 mg qd [11]. The median TTP was 3.32 and 4.21 months, and the median OS 9.82 and 9.71 months, respectively. No difference was detected between doses (p > 0.05), and apatinib at 750 mg po qd was recommended for phase 3 studies.
Future Perspective A phase 2 study using anlotinib for advanced HCC included 50 patients, with 2 cohorts receiving first-and second-line treatments. For the first-line treatment, the 12week PFS rate was 80.8%, with a median TTP of 5.9 months and an OS time of 12.8 months [12]. Second-Line TKI Medication Regorafenib, apatinib, cabozantinib, and ramucirumab were investigated as second-line treatments in phase 3 trials. The RESORCE study included 573 HCC patients with Child-Pugh score A, who failed to respond to but could tolerate sorafenib (≥400 mg daily for at least 20 of the 28 days before discontinuation). Patients were randomized (2:1 ratio) to be given either regorafenib or best supportive care [13]. The median OS times for regorafenib and best supportive care were 10.6 and 7.8 months (HR = 0.63), median PFS times 3.1 and 1.5 months, and response rates 10.6% and 4.1%, respectively.

Consensus-based statement 1: For first-line treatment of locally advanced Barcelona Clinic Liver Cancer (BCLC)
The AHELP phase 3 study using apatinib as the second-line treatment [14] was conducted in 31 centers in China. A total of 393 patients who received at least one line of systemic therapy (including sorafenib-and oxaliplatin-based chemotherapy), were enrolled from April 2014 to May 2017 and randomized at a ratio of 2:1 to receive apatinib at 750 mg or a placebo. The median OS times in the two groups were 8.7 and 6.8 months (p = 0.048), median PFS 4.5 and 1.9 months (p < 0.000), and response rates 10.7% and 1.5%, respectively. The most frequently occurring grades 3 to 4 TRAEs for apatinib were hypertension (27.6%), hand-foot-skin reactions (17.9%), thrombocytopenia (13.2%), and neutropenia (10.5%). Apatinib significantly improved OS and PFS but elicited a greater number of AEs.
The CELESTIAL study enrolled 707 patients with up to two previous systemic and sorafenib HCC treatments, and after randomization (ratio 2:1), they received either cabozantinib or a placebo. The median OS times were 10.2 and 8 months, and median PFS 5.2 and 1.9 months, respectively [15]. The REACH-2 study enrolled 292 patients, with an alpha fetal protein (AFP) level ≥400 μg/L, who failed to respond to sorafenib and were randomized (ratio 2:1) to be given either ramucirumab or a placebo [16]. The median OS times for ramucirumab or placebo were 8.5 and 7.3 months, and median PFS 2.8 and 1.6 months, respectively. The benefits of ramucirumab in the REACH-2 study were more evident in patients with AFP concentrations ≥400 μg/L, pointing to AFP as being potentially predictive. Anlotinib as second-line treatment in a phase 2 study lead to a 12-week PFS rate of 72.5% and a median TTP of 4.6 months, while the median OS time was 18 months [12].
Consensus-based statement 2: After failed first-line sorafenib treatment of locally advanced BCLC stage B and advanced BCLC stage C not suitable for local treatment, options are regorafenib (grade 1 recommendation, evidence level 1); apatinib (grade 2 recommendation, evidence level 1); There has been no established second-line treatment for lenvatinib. Effective post treatments after lenvatinib should be established from clinical practice; ongoing molecular targeted therapy options cabozantinib (grade 2 recommendation, evidence level 1), ramucirumab (grade 2 recommendation, evidence level 1); and anlotinib (grade 3 recommendation, evidence level 3).

Systemic Combination Therapies Systemic Combination Therapies including Molecular Targeted and Immune Checkpoint Inhibitor Medications
In recent years, immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors have shown remarkable efficacy in the treatment of lung cancer and others such as malignant melanoma and lymphoma. Starting in 2017, clinical studies using ICIs to treat advanced HCC were conducted and lead to a breakthrough in second-line therapies. Atezolizumab combined with bevacizumab versus sorafenib investigated in the phase 3 IMbrave150 study showed a significant prolongation of OS and PFS. The median OS times were 19.2 months with atezolizumab-bevacizumab versus 13.4 months with sorafenib, while median PFS times were 6.8 months and 4.3 months, respectively. Grade 3 or 4 treatment-related AEs occurred in 43% of patients treated with atezolizumab-bevacizumab and in 46% of patients treated with sorafenib [17] Based on the outcome of IMbrave150, atezolizumab combined with bevacizumab has become a new option for the first-line treatment of Child-Pugh grade A advanced HCC.
Orient-32 were randomized, open-label, multicenter phase 2 and 3 clinical trials that investigated the safety and efficacy of sintilimab combined with bevacizumab biosimilar drugs as first-line treatments for Chinese patients with advanced HCC compared to sorafenib alone. The latter study randomized patients in a 2:1 ratio with 380 patients given sintilimab combined with the bevacizumab biosimilar and 191 patients given sorafenib. The median follow-up time was 10.0 months. Compared with sorafenib, the median OS was significantly prolonged in the sintilimab combined with the bevacizumab biosimilar group (not estimable vs. 10.4 months, HR 0.57, 95% CI: DOI: 10.1159/000521596 0.43-0.75, p < 0.001), and PFS (4.6 vs. 2.8 months, HR 0.56, 95% CI: 0.46-0.70, p < 0.001) was significantly improved. The incidence rate of TRAEs grade 3/4 was 33.7% for the combination treatment group and 35.7% for the sorafenib group, respectively. Taken together, compared with sorafenib, first-line treatment of sintilimab combined with a bevacizumab biosimilar provided significant clinical benefits for Chinese patients [18].
A phase 2 study (RESCUE) of camrelizumab combined with apatinib for advanced HCC was conducted at 25 centers in China, and results were reported at the ESMO 2020 conference, about patients with advanced HCC who had not been given or therapy had failed with sorafenib or donafenib. Enrolled patients received intravenous camrelizumab 200 mg and apatinib 250 mg qd every 2 weeks. The study included 70 first-line and 120 second-line treatment patients, and 168 of 190 patients (88%) had hepatitis B virus (HBV) infections. According to Response Evaluation Criteria for Solid Tumors (RE-CIST) ver. 1.1, the ORRs evaluated by an independent review board were 34% and 23%; according to modified RECIST (mRECIST) independent assessments, ORRs were 46% and 25%, respectively. The OS rates of 12 months were 75% and 68%, respectively. The updated results were reported at the ASCO 2021 conference; the median OS times were 20.1 months in first-line and 21.8 months in second-line treatments [20]. Overall, 147 (77%) patients had TRAE grade ≥3, most commonly hypertension (34%) and elevated γ-GT (12%). Taken together, combination treatment attempts achieved high response rates in both first-line and second-line treatments for HCC, and the combination of camrelizumab and apatinib may be a promising strategy for the therapy of patients with advanced HCC; further trials should confirm the preliminary data.
In addition, studies on pembrolizumab combined with regorafenib and nivolumab combined with lenvatinib have reported ORRs of 26-54.2%, but reliable survival data have not been published yet [21][22][23]. Updated results were reported in the 2021 ASCO annual meeting, which presented a phase 1b study of regorafenib 120 mg/ day plus pembrolizumab for first-line treatment of advanced HCC with a median OS time of 26.5 months, a median PFS time of 7.5 months, and a median TTP of 8.1 months [24]. Currently, a number of phase 3 studies that are comparing pembrolizumab combined with lenvatinib versus lenvatinib, camrelizumab combined with apatinib versus sorafenib are ongoing.
As prerequisites for the application of combination therapies of molecular targeted drugs and ICIs, patients should be strictly screened for liver function and bleeding risks and concomitant medical disorders. For patients with confirmed HBV or hepatitis C virus (HCV) infections, antiviral therapy should be used to control HBV DNA and HCV RNA titers before checkpoint inhibitor therapy, and active viral hepatitis should be closely monitored during subsequent immunotherapy. Defining the patients risk for TRAEs is critical since combination therapies are more toxic than single-agent therapies and dose adaption may be clinically appropriate. For example, in the study of camrelizumab combined with apatinib, the recommended dose of apatinib was only 250 mg.

Consensus-based statement 3: For first-line treatment of locally advanced BCLC stage B and advanced BCLC stage C patients with Child-Pugh grade A not suitable for local treatment options, the preferred treatment is antiangiogenesis drugs as the main medication combined with immunocheckpoint inhibitors including bevacizumab combined with atezolizumab, or sintilimab combined with the bevacizumab biosimilar (grade 1 recommendation, evidence level 1).
Systemic Therapies including Molecular Targets Combined with Other Drugs A randomized phase 3 clinical study (SEARCH) has shown that sorafenib combined with erlotinib did not improve OS compared to sorafenib/placebo for patients with advanced HCC [25]. The CALGB 80802, another phase 2 study, compared sorafenib combined with doxorubicin versus doxorubicin alone [26]. Median OS times for the combination and monotherapy were 8.9 and 10.5 months, respectively but without a statistically significant difference. A phase 2 study on sorafenib combined with other chemotherapeutics such as gemcitabine [27] and 5-fluorouracil [28] found ORRs of 3-4%, median OS times of 11.6-13.7 months and TTPs of 3.6-8.0 months. When sorafenib was administered with gemcitabine and oxaliplatin, the median OS was 15.7 and for TTP 10.3 months, respectively [29]. These Liver Cancer 2022;11:192-208 DOI: 10.1159/000521596 promising results however should be confirmed by larger clinical studies.

Consensus-based statement 4:
There is currently no evidence that the combination of different molecular targeted drugs or a combination of molecular targeted drugs and chemotherapy can significantly improve survival in advanced HCC (not recommended, evidence level 1).

Molecular Targeted Therapy as Adjuvant Treatment for HCC
Since sorafenib has become the gold standard firstline therapy for patients with advanced HCC, it is reasonable to investigate molecular targeted agents postoperatively in the adjuvant setting [30]. The STORM study, which was a randomized phase 3 study, enrolled 1,114 patients after radical resection. Patients were randomly given either sorafenib (n = 556) or a placebo (n = 558). There were no statistically significant differences in median OS or PFS times between the two groups, and therefore, no improved survival or reduced recurrence rates resulted, probably because of the inclusion of many patients at a low risk of HCC recurrence. In a study from Taiwan that focused on patients at a high risk of recurrence (poor differentiation, microvascular invasion, and satellite nodules), patients were randomized postoperatively to receive either sorafenib 400 mg qd for 4 months or necessary antiviral therapy and supportive care. Here, the rate of recurrence was significantly less in the sorafenib group than in the controls (29.4% vs. 70.7%, p = 0.032). Multivariate analysis suggested that sorafenib was an independent risk factor for postoperative recurrence [31]. A retrospective study of 728 patients conducted by the team of Professor Cheng Shuqun at Eastern Hepatobiliary Hospital revealed that adjuvant sorafenib following radical resection improved OS and PFS times for high-risk patients with microvascular invasion [32]. Other studies performed in China also indicated that adjuvant sorafenib improved OS times in patients with intermediate/advanced BCLC stages B or C, the drug being well tolerated by patients. These studies however may be criticized due to the small sample sizes, the retrospective setting, and the low level of evidence [33][34][35]. A recent multicenter prospective cohort study also revealed that combined use of lenvatinib and transarterial chemoembolization (TACE) can prolong the disease-free survival of HCC patients with high recurrence risk after resection [36]. However, biases resulting from the nonrandomized design and small sample size decreased the reliability of this evidence. Therefore, well-designed,

Molecular Targeted Therapies after Liver Transplantation
Clinical studies have shown that molecular targeted drugs such as sorafenib for systemic treatment or combined with TACE, radiofrequency ablation (RFA), and other local measures can be considered for patients with unresectable HCC relapsing after liver transplantation [37][38][39][40][41]. In the case of first-line sorafenib therapy failure, switching to second-line regorafenib can prolong the survival time [42]. Lenvatinib also seems be effective in patients relapsing after liver transplantation, but confirmative investigations are needed.
After liver transplantation, commonly used immune suppressants are calcineurin inhibitors such as cyclosporine and tacrolimus. It is noteworthy that these drugs are independent risk factors for the recurrence of HCC after a liver transplant [43,44]. The recurrence rate of HCC in liver transplant patients on mammalian target of rapamycin inhibitors is significantly lower than the rate in patients on calcineurin inhibitors. The recurrence rate of HCC is even lower in liver transplant recipients treated with sirolimus. Sirolimus-based immunosuppressive regimens combined with sorafenib are therefore recommended for patients with recurrent HCC who have received a liver transplant [45,46]. ICIs are not recommended because of their immune stimulating effects, their negative effects on immune suppression, and their graft rejection potential.

Consensus-based statement 7:
For patients with unresectable HCC who relapsed after liver transplantation, the options are to use molecular targeted drugs such as sorafenib and regorafenib combined with TACE, RFA and other advanced techniques; a sirolimus-based regimen is recommended as a preferred immunosuppressive treatment (grade 1 recommendation, evidence level 2).
Postoperative adjuvant systemic therapies included sorafenib, as well as doxorubicin, gemcitabine, cisplatin, DOI: 10.1159/000521596 and other chemotherapeutics, for tumors with high-risk factors for recurrence, such as a tumor stage exceeding the Milan indication criteria, poorly differentiated histology, blood vessel invasion, and lymph node metastases. Nonrandomized studies of adjuvant therapies for high-risk patients after liver transplantation showed that sorafenib was more effective than oral gemcitabine. Therefore, sorafenib should be considered as an adjuvant treatment in patients with high-risk factors who are undergoing liver transplantation [47][48][49]. Metuximab (licartin) may also be considered as an adjuvant therapy, but confirmative data of prospective studies are still lacking.
Consensus-based statement 8: For patients undergoing liver transplantation who have any of the following risk factors: exceeded the Milan indication criteria; poorly differentiated histology, blood vessel invasion; and lymph node metastases, adjuvant molecular targeted therapy might be an option to decrease the risk of recurrence (grade 3 recommendation, evidence level 4).

Local Ablation Combined with Molecular Targeted Therapies
RFA is an appropriate treatment to inhibit early-stage HCC, with the advantage of the therapy being less traumatic and deteriorative to liver functions, but being definitively curative and producing reproducible outcomes. Patients with China liver cancer stage Ia HCC and some patients with stage Ib (i.e., single tumor diameter ≤5.0 cm or 2-3 tumors with a maximum diameter of ≤3.0 cm), as well as patients with no vascular invasion, no bile duct, adjacent organ invasion, distant metastasis, and a liver function Child-Pugh grade A or B are candidates for RFA [50]. The aim of an upcoming clinical trial, which will add molecular targeted therapies to RFA, is the prevention of disease recurrence. However, based on current evidence, the use of molecular targeted drugs for adjuvant treatment after RFA cannot be recommended. In the STORM study 1,114 patients from 202 centers were randomized in a ratio of 1:1 to postoperative adjuvant sorafenib or a placebo following surgical resection (n = 900) and RFA (n = 214). No difference was found in the median PFS between the two groups (33.3 and 33.7 months, respectively) [30]. The role of newer molecular targeted agents such as lenvatinib and regorafenib has to date not yet been defined clinically. Palliative ablation therapy for advanced HCC is currently under investigation. Nevertheless, combining TACE ablation and sorafenib has shown longer survival for patients with BCLC stage C [51].

Consensus-based statement 9: For patients with earlystage HCC; adjuvant molecular targeted therapies after local ablation is not recommended (not recommended, evidence level 2). External Beam Radiation Combined with Molecular Targeted Therapy
Clinical trials on radiotherapy combined with molecular targeted therapy mainly included patients with intermediate and advanced stage disease. A phase 2 study enrolled 40 patients with locally advanced HCC that was unresectable and unsuitable for TACE. Patients received conventional radiotherapy and sorafenib during and after radiation until disease progression [52]. The ORR of the entire group of patients was 55% at 1 month after radiotherapy and 2-year OS rates were 32% and 39%, respectively. The incidence of ≥2 grade hepatotoxicity was 35%, including 3 deaths, indicating a potential risk of the concomitant treatment strategies. A retrospective analysis found that the incidence of grade 3 TRAEs was high [53]. The RTOG1112 phase 3 trial which compared sorafenib versus sorafenib to treat patients with stereotactic body radiotherapy (SBRT), who had HCC that was locally advanced, is ongoing and the outcome is eagerly awaited.
A South Korean phase 2 study investigated sequential setting enrolled 47 patients with BCLC stage C [54]. Patients received conventionally fractionated radiotherapy for intrahepatic lesions. Continuous 5-FU and tetrahydrofolate hepatic artery pump chemotherapy were given for 5 days before and after radiotherapy, and oral sorafenib was started 4 weeks after radiotherapy. The median OS time of the entire group was 24.6 months (95% CI: 10.9-38.4), and the AEs were manageable. A Japanese retrospective analysis also reported that intrahepatic radiotherapy combined with hepatic artery pump chemotherapy followed by sequential sorafenib improved survival [55].

Consensus-based statement 10: For patients with inoperable BCLC stages B or C without extrahepatic metastases, concurrent radiotherapy and sorafenib should be used cautiously due to toxicity. Sequential sorafenib following radiation can be considered, but confirmative large clinical studies are still missing (grade 3 recommendation, evidence level 3).
A prospective study compared sorafenib combined with intrapulmonary SBRT versus SBRT alone in 60 patients with lung metastases of HCC [56]. Median PFS and OS times were improved by the combination therapy with acceptable toxicity, suggesting that SBRT could be safely and effectively used for oligo-metastatic disease together with targeted therapies. A retrospective analysis from Fudan University Zhongshan Hospital also found that patients with lung metastases of HCC who received radiotherapy (helical tomotherapy) combined with sorafenib had a significantly better outcome compared to those patients who received only radiotherapy (median OS time: 29.6 vs. 23 months, p = 0.031) or targeted therapy alone (median OS: 29.6 months vs. 25 months, p = 0.018) [57].

Consensus-based statement 11: For patients receiving molecular targeted therapy for extrahepatic metastases the addition of SBRT is an option in the case of oligo-metastatic disease (grade 3 recommendation, evidence level 3).
TACE Combined with Molecular Targeted Therapy TACE alone is appropriate therapy for some patients that exhibit early-stage or mid-stage HCC (BCLC stages 0, A or B; or stages I-II in the Chinese Guidelines for the Diagnosis and Treatment of this disease [2020]), who are not suitable for surgical resection because of reduced liver functions. Adding sorafenib to drug-eluting bead TACE (DEB-TACE) failed to prolong the TTP [58].
Adding sorafenib to DEB-TACE also failed to improve PFS [59] in the TACE2 trial, a phase 3 study that included 399 patients with BCLC stage B from 20 UK hospitals. Median PFS for DEB-TACE plus sorafenib was 238 days (95% CI: 221.0-281.0 days) and for DEB-TACE plus placebo 235 days (95% CI: 209.0-322.0 days), respectively, resulting in a HR of 0.99 (95% CI: 0.77-1.27, p = 0.940). In contrast, a Japanese TACTICS phase 2 study that used an uncommon design indicated that TACE plus sorafenib could improve PFS in patients with early-stage and midstage unresectable HCC but without vascular invasion and extrahepatic metastases, suggesting grade 3 level recommendation [60]. In this study, 197 patients with unresectable HCC but no extrahepatic metastases were enrolled in 33 hospitals. The diameter of tumors was ≤10 cm, and the number of lesions should have been not more than 10, without vascular invasion. Thirty eight percent of the patients had BCLC stage A and 50% stage B, respectively. The main study endpoint was PFS defined by the time to untreatable (unTACEable) progression. This unique study endpoint has the potential of delaying the time to change treatment strategies, reflecting todays TACE real-world practice, meaning that if new lesions appear in the liver during TACE treatment, TACE would be continued and thus prolong the time of effective therapy. The median PFS time reached 25.2 months by adding sorafenib to conventional TACE versus 13.5 months for conventional TACE, respectively, resulting in a HR of 0.59 (95% CI: 0.4-0.87, p = 0.006).

Consensus-based statement 12: For patients with unresectable early and mid-stage HCC, TACE combined with sorafenib is a treatment option since it can improve PFS (grade 3 recommendation, evidence level 2).
For those patients with good liver functions, TACE is appropriate therapy. Several retrospective studies and meta-analyses have shown that TACE combined with sorafenib improved clinical outcomes compared to TACE treatment alone [61][62][63]. The systematic review and meta-analysis reported by Zhang et al. [63] showed that TACE combined with sorafenib increased ORR (OR 3.59, 95% CI: 1.74-7.39; I 2 = 21%, p = 0.001) and the disease control rate (OR 4.72, 95% CI: 1.75-12.72; I 2 = 56%, p = 0.002) compared to TACE treatment alone in patients who had portal vein tumor thrombosis and in addition improved the OS at 6 months and 1 year (HR 0.62; 95% CI: 0.51-0.75; I 2 = 30%, p < 0.000).
Qiu and colleagues [64] retrospectively analyzed 251 cases of advanced HCC with extrahepatic metastases treated with various TACE-based combinations including TACE/sorafenib and TACE/apatinib. It was demonstrated that adding molecular targeted therapies to TACE provided better outcomes compared to TACE treatment alone. Furthermore, it was found that TACE combined with sorafenib prolonged TTP (2.7 months vs. 2.1 months, p = 0.011) [65] but that OS (9.1 months vs. 6.7 months, p = 0.210) was not significantly different to TACE therapy alone in patients with HCC with portal vein tumor thrombosis and/or extrahepatic metastases. Nonetheless, to clarify these conflicting results and to determine the value of TACE combinations, prospective phase 3 studies should be performed [66].

Molecular Targeted Drug Dose Selection and AE Management
Dose Selection A number of phase 3 and post-marketing real-world studies have shown that standard doses of sorafenib were well tolerated [7,8,67,70], and it was recommended to start with a sorafenib standard dose. However, for lenva-tinib, the incidence of treatment-related treatment-emergent AEs of grade ≥3 seemed to have been higher than that of sorafenib (57% vs. 49%) in the REFLECT study [9]. High rates of lenvatinib dose reductions and discontinuations have been observed in several other studies mainly due to thyroid dysfunction, fatigue, and appetite loss as well as albumin-bilirubin grade 2 [71,72], while relative dose intensities (RDIs) of ≥75% for 8 weeks [73] and ≥70% for 4 weeks [74,75] were noted to be factors for favorable responses of lenvatinib therapies for HCC.
The toxicity profile of regorafenib in HCC is similar to that seen for advanced colorectal cancer [13]. Hand-footskin reactions and fatigue that occur during the early phase of therapy may lead to the early termination of regorafenib. Results of a number of phase 2 studies have shown that an appropriate reduction of the initial dose in the first cycle and adjustment to the standard dose in the second and subsequent cycles did not reduce efficacy of regorafenib but were less toxic in treating advanced colorectal cancer [69,76,77]. Nonetheless, reliable real-world data are yet not available for advanced HCC in China. In Japan and South Korea, however, clinical practice seems to generally adjust the second-line setting of regorafenib initially to 120 mg or 80 mg for patients with Child-Pugh grade B or C liver functions, renal insufficiency, body weight <50 kg, or with grade 2-3 TRAEs during first-line sorafenib therapy [78,79]. OS and PFS times however were significantly longer in patients who received a ≥50% RDI of regorafenib in the first month compared to patients who received a <50% RDI [80]. Clinically relevant toxicity data obtained from the prospective large scale real-world RE-FINE study were reported at ASCO 2020. Patients were enrolled (500), mainly having been pretreated with sorafenib, with the majority having a PS score of >1 and a liver function of Child-Pugh stage B. Patients were given a standard dose of 160 mg regorafenib in 57%, 120 mg in 13%, 80 mg in 28%, and 40 mg in 2% of them as starting medication, respectively. The incidence of TRAEs was 66%, and of grades ≥3 was 21%, which was lower than in phase 3 studies (93% and 50%, respectively). Seventy five percent of patients developed TRAEs during the first 8 weeks of treatment, and 83% underwent dose reduction. The median PFS was similar to that of the RESORCE study (3.7 months vs. 3.1 months), and the median OS was longer than in the RESORCE study (13.2 months vs. 10.6 months) [81].
Consensus-based statement 15 TRAEs of Molecular Targeted Therapies For molecular targeted drugs used to treat HCC, common AEs include fatigue, diarrhea, hand-foot-skin reactions, hypertension, anorexia, weight loss, proteinuria, nausea, vomiting, hoarseness, hypoproteinemia, anemia, a decrease in platelet counts and white blood cell numbers, and abnormal liver functions. Life-threatening TRAEs included congestive heart failure, myocardial ischemia or myocardial infarction, a hypertensive crisis, gastrointestinal perforation/bleeding, and airway and intracranial hemorrhage. The incidence of TRAEs under the targeted drugs has been 61.0% in a recent retrospective Chinese study [82]. Treatment modifications, such as drug suspension, dose reduction, or permanent withdrawal should be undertaken according to the severity of TRAEs. Before initiating therapies, patients should be informed regarding the potential occurrence of TRAEs and appropriate preventative measures taken including exercise, skin ointment, diet, and blood pressure monitoring, as well as doctor consultations.
Consensus-based statement 16: For TRAEs, general principles of pre-medication should be obeyed during and between therapies with respect to potential hand-foot-skin reactions, hypertension, diarrhea, and to other group toxicities of molecular targeted therapies. Adequate treatment modifications should be initiated such as treatment delay, dose reduction or withdrawal of medication. For serious TRAES, interdisciplinary advice is critical (grade 1 recommendation, evidence level 1).
Use of Traditional Chinese Medicine to Manage Drug Toxicities Traditional Chinese medicine (TCM) can be beneficial in treating skin and mucosal AEs. External washing and treating hand-foot-skin toxicities with TCM compounds may reverse local heat, resolve dampness, improve the blood microcirculation, and remove micro-thrombosis, resulting in a response rate of 80-95%. It also helps in the treatment of rash and mucositis, maintaining drug dosage and avoiding treatment withdrawal [83]. TCM may be appropriate in alleviating treatment-related diarrhea. Since TCM compounds sooth the liver, tonify the spleen, clear dampness, and promote diuresis, they can be effective in relieving diarrhea. Studies also suggest that TCM may synergistically increase the antitumor effect of molecular targeted drugs [84], thus providing another rationale for combining oral TCM with molecular targeted therapies. In addition, TCM and acupuncture are commonly used to relieve cancer-related fatigue [85,86].
Consensus-based statement 17: TCM can be used to treat molecular targeted drug-related skin and mucosal toxicity and molecular targeted drug-related diarrhea (grade 1 recommendation, evidence level 2).
Consensus-based statement 18: TCM has definite efficacy in treating cancer-related fatigue, but for fatigue caused by molecular targeted therapy patients should be first introduced to clinical trial programs (grade 2 recommendation, evidence level 1).

Efficacy Evaluation of Molecular Targeted Therapies
Evidence RECIST 1.1 guidelines are used internationally to measure the treatment effect produced by conventional chemotherapy of solid malignant tumors. But, today, commonly applied molecular targeted drugs such as sorafenib and lenvatinib display their antitumor effects mainly by inhibiting tumor angiogenesis. CT or MRI, apart from pure volume reduction, usually reveals an impact on arterial blood flow, tumor necrosis, and liquefaction in tumors. Additionally, due to tumor necrosis after local treatments such as ablation, embolization, and radiotherapy, CT/MRI images may look unaltered or even show an increased tumor volume. Bearing this in mind, RECIST, which is based essentially on the maximum tumor diameter, may have shortcomings in measuring the actual efficacy of molecular targeted therapies and may not reflect specific response patterns.
Therefore, in 2009, the American Association for the Study of Liver Diseases proposed mRECIST for a comprehensive evaluation of selective HCC treatments using CT/MRI measurements in the arterial phase of the maximum diameter of the enhanced region within a tumor. Studies have shown that ORR assessed by mRECIST is an independent prognostic factor for molecular targeted therapies of HCC. Comparing RECIST with mRECIST in the efficacy evaluation of sorafenib, ORR increased from 6.5% to 9.2% and up to 17.5% [68,87]. The OS of patients responding to lenvatinib or sorafenib was prolonged by up to 22.4 months, 11 months more than for nonresponders (p < 0.001) [88]. In the case of local treatment using mRECIST, responders compared to nonresponders had a 61% decreased risk of death (p < 0.000) [89], and such defined responders had a better prognosis than those assessed by RECIST [90]. DOI In summary, mRECIST compared to RECIST was better able to reflect short-term efficacy and may also have an advantage in predicting long-term survival and thus is a promising guiding factor for clinical practice in evaluating the efficacy of molecular targeted therapy for HCC. It is recommended for the selection of target lesions to avoid necrotic areas and to choose instead enhanced areas in the arterial phase which can be repeatedly measured. In general, portal vein tumor thrombosis and ascites should not be regarded as target lesions but can be followed up as nontarget lesions.
Consensus-based statement 19: RECIST 1.1 are often used for efficacy evaluation in HCC patients under molecular targeted therapies. One option comprises the mRE-CIST, reflecting short-term efficacy better and should be followed in combination with RECIST 1.1 (grade 1 recommendation, evidence level 1) (Table 4).

Predictors in Using Molecular Targeted Therapies
HCC markers are mainly used for diagnoses. The clarification of their predictive values for molecular targeted treatment, in particular with sorafenib, is under investigation. TRAES to sorafenib correlate with the prognosis of patients with HCC, most prominently with hand-foot-skin toxicities. A recent meta-analysis involving 1,017 patients treated with sorafenib found that hand-foot-skin reactions correlated significantly with efficacy and TTP [91]. In addition, a retrospective analysis based on SHARP and ORIENTAL phase 3 studies showed that sorafenib was more effective in treating HCV-related to HCC compared to patients infected with hepatitis B virus, probably because of inflammation caused by persistent replication of the virus [92]. Patients suffering from a hepatitis B infection in general received antiviral treatment, leading to low virus replication.
In terms of serological markers, patients receiving sorafenib whose AFP level dropped by more than 20% within 6-8 weeks of treatment had better outcomes and prognosis. An early decline of the AFP level resulted in a higher ORR (33% vs. 8%) and longer OS (15.3 months vs. 4.1 months) [93]. The SHARP and ORIENTAL studies found that patients with a lower peripheral blood neutrophil to lymphocyte ratio had a longer OS and generally were more likely to benefit from sorafenib [92], probably reflecting the inflammation state and correlation between pro-tumor inflammation and the antitumor immune response. Nevertheless, it can be argued that no definition standard yet exists for the NLR-threshold and that prediction value need further clarification.
Another study conducted in Japan found that increased circulating fibroblast growth factor 19 and decreased angiopoietin-2 serum concentrations exhibited in combination an independent association with PFS under lenvatinib therapy of HCC patients [94]. Another Chinese study suggested that fibroblast growth factor receptor 4 expression levels and Treg infiltration in tumors might serve as biomarkers for screening HCC patients, who would be suitable for lenvatinib plus anti-PD-1 combination therapies [95]. For anlotinib, the C-X-C motif chemokine ligand 1 (CXCL1) plasma concentration has been proposed to be an efficacy predictor for HCC treatments [12].

Role of Multidisciplinary Teams
A comprehensive diagnosis and treatment concept for malignant tumors has become a critical issue. The existence of a multidisciplinary team (MDT) helps to overcome the limitations of single disciplinary decisions to guarantee broader knowledge and experience based case discussions and finally evidence-based individualized diagnosis, treatment, and follow-up concepts. HCC is a heterogeneous neoplasm, differing in its origins and biological nature. These factors underline the importance of MDT, which only can provide the required evidencebased comprehensive recommendations on tumor characteristics and the clinical stage, molecular pathological diagnosis, and treatment options. Patients suffering from mid-stage and advanced HCC often require multidisciplinary therapies, which combine local and systemic treatment options [96]. More than 90% of HCC patients have underlying chronic liver disease or cirrhosis and because of the toxicity risk of tumor therapies, a liver specialist or gastroenterologist should definitely be a part of HCC-MDT [97]. Needless to say, drug-related toxicity may require expert assistance from various clinical disciplines such as hepatology, dermatology, and TCM.
Consensus-based statement 23: For the determination of evidence based treatment strategies in HCC, MDT should definitely be established in any centers dealing with liver cancer patients (grade 1 recommendation, evidence level 1).

Conclusions
In recent years, the treatment of liver cancer has undergone rapid changes, and many therapeutic drugs and new therapeutic technologies have emerged. However, targeted antiangiogenic drugs remain the backbone of systemic treatment for advanced HCC, although atezolizumab combined with bevacizumab has become a new option for the first-line treatment of advanced HCC.
While looking forward to the development of more antiangiogenic drugs with low toxicity and high efficacy, it is an important direction for liver cancer therapy to explore continuously other therapeutic targets in basic research and to find more specific targeted drugs. At the same time, on the basis of targeted drugs, how to effectively integrate the existing and emerging new therapeutic technologies is a major challenge. In the above chapter, we discussed recent research evidence and clinical diagnosis and treatment experience to provide consensus statements. We also look forward to carrying out more researcher-initiated multidisciplinary studies to provide more evidence-based proposals for the optimization of targeted therapy-based advanced liver cancer treatments.

Conflict of Interest Statement
Jia Fan is an editorial board member of Liver Cancer. The remaining authors have no conflicts of interest to declare.

Author Contributions
Jianqiang Cai served as the principal guidance for this consensus. All the authors contributed to the preparation of the paper and have read and approved the final manuscript for publication.

Data Availability Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.