Chinese expert consensus on clinical application of molecularly targeted drugs for hepatocellular carcinoma (2022 edition)

To the Editor: Primary liver cancer is one of the most common malignant tumors in China. In 2020, 410,038 new cases of liver cancer and 391,152 deaths due to liver cancer were reported in China, which places liver cancer as the second most common cancer-related cause of death in China; of these cancers, hepatocellular carcinoma (HCC) accounts for 85–90%.[1] HCC poses a significant threat to the lives and health of Chinese people. This consensus discusses only molecularly targeted therapy for HCC. HCC has an insidious onset, high malignancy, and rapid progression, and at the time of diagnosis, most patients with HCC in China are at a locally advanced stage or have distant metastasis. Both domestic and foreign guidelines recommend systemic treatment for these patients. The Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2022 edition)[2] recommend targeted drugs for patients with advanced HCC, while the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Hepatobiliary Cancers (V5, 2021) recommend additional types of systemic treatment options.[3] Many targeted drugs have been developed for different treatment purposes and for different patient populations, and the way in which these therapies are selected to achieve a maximum benefit has been left up to individual clinicians due to the absence of authoritative guidelines. The Chinese Association of Liver Cancer and Chinese Medical Doctor Association arranged experts in relevant fields to compile the Chinese expert consensus on the clinical application of molecularly targeted drugs for hepatocellular carcinoma (2020 edition) based on relevant clinical studies and treatment experience after many discussions and revisions. Since then, the National Medical Products Administration (NMPA) has approved many new targeted drugs for HCC based on updated evidence. To better guide clinical practice, the Chinese Association of Liver Cancer and Chinese Medical Doctor Association has improved and updated the Chinese expert consensus on the clinical application of molecularly targeted drugs for hepatocellular carcinoma (2022 edition) for clinicians’ reference. The consensus is intended for use primarily by doctors involved in the treatment of patients with HCC. We present the following article in accordance with the Reporting Items of Practice Guidelines in Healthcare (RIGHT) reporting checklist. Recommendation level can refer to Supplementary Tables 1 and 2, https://links.lww.com/CM9/C198. The main recommendations of the consensus are as follows: The first-line targeted drugs for advanced HCC are sorafenib, lenvatinib, bevacizumab combined with atezolizumab, donafenib, and IBI305 combined with sintilimab (Ib, A). The second-line targeted drugs are regorafenib, apatinib, and cabozantinib (Ib, A). For patients with early HCC with a high risk of recurrence after surgery (with microvascular invasion, satellite nodules, etc.), molecularly targeted drugs with immune checkpoint inhibitors (ICIs) or local therapy are recommended as adjuvant therapy to prevent postoperative recurrence (IIb, B). For patients with inoperable intermediate and advanced HCC with conversion possibility, a combined treatment based on molecularly targeted drugs is feasible, and it is recommended that these patients be included in clinical trials (IIb, A). After successful conversion, molecularly targeted drugs should be stopped for more than 1–2 weeks before liver resection, while bevacizumab should be stopped for more than 4–6 weeks (III, A) and ICIs should be stopped for more than 3 months before liver transplantation (III, A). At present, the use of targeted drugs for neoadjuvant therapy is still in the exploratory stage. It is suggested that patients with a high risk of HCC recurrence be actively included in relevant clinical trials (IV, B). Molecularly targeted drugs should be used as basic drugs for the treatment of patients with China liver cancer stage III HCC (IIb, A). It is also recommended that local treatment be added to strengthen the control of intrahepatic lesions or that other drugs be added to strengthen the control of systemic lesions (IIb, B) according to the level of liver function. For patients with liver cancer with Child–Pugh class A, targeted drugs combined with immunotherapy are recommended, and it is also recommended that these patients actively participate in clinical trials to explore the best combination (Ib, A). For patients with liver dysfunction (Child–Pugh B8–9), it is recommended that molecularly targeted drugs be used carefully for salvage treatment according to their individual conditions and that their liver function be closely monitored to avoid serious impairment in liver function (III, c). Molecularly targeted drug therapy is not recommended for patients with end-stage HCC (III, d). For patients with impaired renal function, it is recommended that molecularly targeted drugs be used carefully according to their individual conditions and that their renal function be closely monitored to avoid serious impairment in renal function. Generally, patients with mild or moderate renal impairment do not require dose adjustment (III, B). There are currently no clear indicators that can be used to predict the efficacy of targeted drugs. After progression is observed by imaging during treatment with first-line targeted drugs, a timely comprehensive evaluation should be performed to determine the appropriate second-line treatment (IIb, B). Physicians should educate patients with HCC and fulfill the obligation of comprehensive notification when using molecularly targeted drugs. Some adverse events (AEs) with no obvious symptoms should be followed-up in a timely manner. Patients require guidance so that they can take measures to prevent AEs. Medical staff should monitor and manage these patients in a timely manner to improve patient compliance and quality of life to maximize their benefits to the patients (III, A). After sorafenib, lenvatinib, or donafenib is used as a first-line treatment, regorafenib, apatinib, or cabozantinib (Ia, A) can be used as a second-line treatment; after first-line treatment with atezolizumab plus bevacizumab or sintilimab combined with a bevacizumab biosimilar, molecularly targeted drugs (first-line or second-line) (III, A) are second-line treatment options, and patients are recommended to participate in clinical trials. It is recommended that differentiated treatment strategies be adopted for the targeted treatment of intermediate-stage HCC. If the efficacy of transarterial chemoembolization (TACE) cannot meet expectations, switching to or combining TACE with systemic antitumor therapy (IIb, A) should be considered. For intermediate-stage HCC with a high tumor load, we should consider changing the treatment concept and use targeted drugs or combined immunotherapy instead of TACE (III, B). Many clinical studies have demonstrated that molecularly targeted drugs are effective treatments for advanced HCC, as they have good objective response rate (ORRs) and obvious survival benefits. Preliminary evidence exists for a number of targeted drugs that were only recently approved by the National Medical Products Administration (NMPA). This consensus combines phase III clinical research data of molecularly targeted drugs for the treatment of advanced HCC, data from clinical usage after listing, the practical experience of experts and scholars, and the knowledge about the use of antiangiogenic drugs and presents opinions and suggestions on how to reasonably, safely, and effectively select and apply targeted drugs, which can be provided to clinicians as a reference. Targeted therapy for HCC is developing rapidly, and new drugs and treatment methods are emerging regularly. The optimal administration methods, dose intensity, exploration of drug endpoints, types and extent of adverse events, and relevant prevention and treatment measures of various molecularly targeted drugs require further close observation and accumulation of evidence to improve the clinical use of these medications. Accordingly, we have updated and supplemented this consensus, and it will be regularly updated. Funding This work is supported by grants from the State Key Project of the National Natural Science Foundation of China (No. 81730097), the Clinical Science and Technology Innovation Project of Shanghai Shenkang Hospital Development Center (Joint Project of Emerging Frontier Technology) (No. SHDC12018116), and the Clinical Research Plan of Shanghai Hospital Development Center (No. SHDC2020CR1004A). Conflicts of interest None.