Liyang Sun, Yangxun PAN A, Minshan Chen (Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China)
Corresponding author: Chen Minshan
E-mail:[email protected]
Prof. Minshan Chen
Director of the Department of Liver Surgery, Sun Yat-sen University Cancer Center
Director of the Institute of Liver Cancer, Sun Yat-sen University
Chairman of the Liver Cancer Committee of the Chinese Anti-Cancer Association
Honorary Chairman of the Liver Cancer Comprehensive Treatment Committee of the Chinese Geriatric Health Care Association
Vice Chairman of the Liver Cancer Professional Committee of the Chinese Medical Doctor Association
Vice Chairman of the Liver Cancer Expert Committee of the Chinese Society of Clinical Oncology
Former chairman of the Liver Cancer Branch of Guangdong Medical Association
Honorary Chairman of the Liver Cancer Professional Committee of Guangdong Anti-Cancer Association
Member of the Liver Surgery Group of the Surgery Branch of the Chinese Medical Association
Member of the Liver Cancer Group of the Hepatology Branch of the Chinese Medical Association
Member of the Liver Cancer Group of the Oncology Branch of the Chinese Medical Association
Primary liver cancer is one of the most common malignant tumors worldwide, and about 85% of them are hepatocellular carcinoma (HCC). In recent years, experts and scholars at home and abroad have carried out a lot of clinical work, and put forward a series of potential therapeutic drugs and programs, which are expected to further improve the efficacy and long-term survival of liver cancer patients. This article reviews the research status of liver cancer treatment in 2023 from three major directions: perioperative surgical treatment, systemic drug therapy and multidisciplinary combination therapy.
【Keywords】hepatocellular carcinoma, surgery, systemic therapy, comprehensive treatment
The high incidence of primary liver cancer is a serious public health problem in mainland China, of which hepatocellular carcinoma (HCC) accounts for about 85%, and is the second most common malignant tumor in mainland China and the second leading cause of cancer mortality [1]. In recent years, with the joint efforts of experts and scholars at home and abroad, the clinical treatment of liver cancer has undergone significant changes, and a variety of new treatment methods have emerged, which have greatly improved the treatment effect. The disease-centered and surgical resection-oriented multidisciplinary diagnosis and treatment system has been widely recognized by many centers in China, and has been continuously promoted and improved in clinical practice. The purpose of this article is to review and analyze the current status and problems of liver cancer treatment research in 2023.
1. Surgical treatment
Surgical resection, as the treatment method with the best therapeutic effect, is at the core of the comprehensive treatment model of liver cancer. The 2023 American Association for the Study of Liver Diseases guidelines for liver cancer [3] and the 2023 National Comprehensive Cancer Network guidelines for liver cancer diagnosis and treatment [4] have expanded the indications for surgical resection of liver cancer for the first time. Surgical resection may be considered in selected patients with BCLC stage B and Vp1 and Vp2 portal vein cancer thrombosis or those with rigorous screening Child-Pugh grade B after multidisciplinary discussion at a large, experienced liver center. However, the expansion of surgical indications has not been smooth sailing, and a combination of other therapies is required to ensure efficacy. With the advancement of interventional therapy and drug therapy, the in-depth exploration of transformational therapy, neoadjuvant therapy and postoperative adjuvant therapy and the multidisciplinary comprehensive treatment model of liver cancer have become research hotspots in 2023.
1.1 Conversion therapy
Most of the patients with liver cancer in mainland China are in the middle and advanced stages when they are first diagnosed, and stage I radical resection is not possible, and the initial operable resection rate is only 15%~30%. Conversion therapy has brought hope to some patients with initially unresectable liver cancer who have been evaluated before surgery, and the 5-year survival rate of patients who have successfully converted and achieved surgical resection therapy has been significantly improved.
Previous studies have shown that the combination of local interventional therapy + targeted therapy and immunotherapy has better efficacy [5-9], and is currently the most commonly used regimen for conversion therapy. At the 2023 European Society for Medical Oncology (ESMO) Annual Meeting, a prospective phase II clinical trial (NCT05166772) from Tianjin Medical University Cancer Hospital was announced, focusing on hepatic arterial infusion Chemotherapy (HAIC) in combination with donafenib and sintilimab in the first-line treatment of unresectable hepatocellular carcinoma[10]: The objective response rate (ORR) was 82.1% based on modified response evaluation criteria in solid tumors (mRECIST) , the conversion success rate was 64.3% (18/28), and the median progression-free survival (PFS) time was 10.2 months. In terms of conversion therapy for advanced liver cancer, there are many clinical studies of local interventional therapy combined with first-line drug therapy in progress, but no matter what kind of drug is combined, local therapy plays an irreplaceable role in it.
Also presented at this year's ESMO Annual Meeting, the results of a prospective phase II clinical study (ChiCTR1900023914) from the PLA General Hospital showed that sintilimab in combination with lenvatinib had good efficacy and safety in the first-line treatment of unresectable liver cancer, with an ORR of 54 percent and a conversion success rate of 51 percent in 100 patients with evaluable efficacy, and 47 percent of patients underwent liver resection [11]. This is a reasonable and promising conversion treatment option, especially for patients with severe cirrhosis of portal hypertension, a history of gastrointestinal bleeding, or a high risk of bleeding.
In view of the fact that most of the liver cancer in mainland China is no longer resectable at the time of treatment, it has become a hot topic in clinical research of liver cancer in mainland China to increase the surgical resection rate and improve the efficacy through conversion therapy. With the wide application of HAIC therapy and the improvement of the effect of targeted therapy and immunotherapy, translational therapy has become a feature of clinical treatment of liver cancer in mainland China, and a large number of clinical studies and methods are ahead of the world. However, the ultimate goal of conversion therapy is to improve the prognosis of liver cancer, not simply to achieve radical resection, so for some patients with good transformation effect and stage decline to meet the technical and oncological resectable criteria, how to decide the next treatment plan is an urgent evidence-based problem at this stage. The ongoing TALENTop study aims to evaluate the efficacy and safety of hepatectomy in patients with hepatocellular carcinoma complicated with macrovascular invasion after atezolizumab plus bevacizumab [12] to explore the value and significance of hepatectomy in patients with advanced hepatocellular carcinoma after conversion therapy.
1.2 Neoadjuvant therapy
Neoadjuvant therapy refers to the treatment of patients who are technically resectable (R0 resection, sufficient remaining liver volume) but have high-risk risk factors for recurrence, and carry out systemic therapy or local therapy before surgery to shrink the tumor, eliminate the invisible lesions as soon as possible or increase the surgical margins, so as to reduce the surgical risk and postoperative recurrence rate. The requirement for regimen selection is to obtain both a fast and good treatment effect while maintaining the patient's liver function condition to complete the intended surgery.
At the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, the final results of a phase III, prospective, randomized controlled clinical trial (NCT03851913) led by our center in 7 centers in China were announced. fluorouracil and oxaliplatin) chemotherapy + HAIC in patients with resectable BCLC stage A and B HCC that exceeds the Milan criteria [13]. A total of 392 patients met the enrollment criteria in the study, including 195 patients in the neoadjuvant FOLFOX+HAIC group (treatment group) and 197 cases in the direct surgery group (control group) before liver resection, and were included in the intention-to-treat (ITT) population analysis, and 181 patients in the final treatment group and 184 patients in the control group received planned follow-up treatment, and were included in the per- protocol, the median PFS time in the treatment group and control group was 17.4 months and 9.8 months in the ITT population, and 22.7 months and 10.2 months in the treatment group and control group in the PP population, respectively. From the perspective of evidence-based medicine, this study provides a high level of evidence that preoperative neoadjuvant FOLFOX-HAIC can bring survival benefits to patients with resectable BCLC stage A and B liver cancer beyond Milan standards, explores a safe and effective treatment strategy for patients with poor surgical efficacy, and updates the concept of preoperative neoadjuvant therapy. It is expected that in the future clinical practice, the dosing regimen and process of HAIC therapy can be further optimized, and more accurate neoadjuvant beneficiary groups can be explored, so as to bring hope to more liver cancer patients. In addition, prospective phase II clinical studies of tislelizumab in combination with lenvatinib [14] and camrelizumab in combination with apatinib [15] in the perioperative treatment of resectable liver cancer with high risk of recurrence have shown encouraging efficacy and good tolerability. Interim results from a phase I.b study of stereotactic radiosurgery (radiotherapy) combined with tislelizumab neoadjuvant for resectable liver cancer (Notable-HCC) were also reported at the 2023 ESMO Annual Meeting, in which all 10 patients were enrolled in neoadjuvant therapy and surgical resection without surgical delay, with ORRs of 30 percent (RECIST v1.1) and 60 percent (mRECIST) [16]. This adds a potentially viable option to neoadjuvant therapy.
1.3 Adjuvant therapy
The characteristics of low resection rate and high recurrence rate of liver cancer have promoted the exploration of postoperative adjuvant therapy by many experts and scholars. With the advancement of interventional therapy and drug therapy, the effect of postoperative adjuvant therapy has been significantly improved. At the same time, there are also a series of controversies in the application of adjuvant therapy, and there is no recognized adjuvant treatment regimen, and there are differences in domestic and foreign guideline recommendations, which need further evidence-based.
Preliminary results from a multicenter phase III study of FOLFOX+HAIC in the postoperative adjuvant treatment of liver cancer complicated with microvascular invasion were presented at the 2022 ASCO Annual Meeting, and finally published in the Journal of Clinical Oncology in 2023 [17]. This study showed that postoperative adjuvant FOLFOX+HAIC significantly improved the disease-free survival time of patients with microvascular invasion of hepatocellular carcinoma. Results from another high-profile multicenter, randomized controlled, phase III clinical study of postoperative adjuvant therapy (Imbrave050) were published in the journal Lancet in October 2023 [18]. A total of 668 patients with liver cancer at high risk of recurrence after radical surgery or ablation were recruited from 134 medical institutions in 26 countries or regions around the world, and randomly assigned 1:1 to atezolizumab combined with bevacizumab (T+A) or active surveillance follow-up group, with a median follow-up of 17.4 months and 17.6 months, respectively, with 110 (33%) in the T+A group and 133 (40%) in the active surveillance follow-up group (40%) The median recurrence-free survival time was not reached in both groups, with 12-month recurrence-free survival rates of 78% and 65%, respectively (P=0.012), and similar improvements were observed in the recurrence-free survival assessed by the investigators, and this benefit was basically consistent in the key clinical subgroups, and the safety analysis showed that the incidence of adverse events in the T+A group and the active monitoring and follow-up group were 98% and 62%, respectively, most of which were grade 1~2, and the incidence of grade 3~4 adverse events was 41%, respectively and 13%. The above results showed that in patients with a high risk of recurrence after radical resection or ablation, adjuvant therapy with atezolizumab combined with bevacizumab could significantly improve the recurrence-free survival status of patients with a controllable safety profile. The IMbrave050 study is the first Phase III clinical study to report positive results in adjuvant drug therapy for liver cancer after surgery, and the publication of its results has greatly promoted the progress of adjuvant therapy for liver cancer after surgery. However, the results of the study only showed a significant difference in recurrence-free survival, and the overall survival (OS) rate is still to be announced. Therefore, there is still a great deal of controversy as to whether this regimen should be routinely used for adjuvant therapy after surgery, and a more comprehensive evaluation of the benefits, costs, and risks of treatment is needed, and there is still no sufficient clinical reason for the routine use of other targeted therapies and immunotherapies for adjuvant therapy. But in any case, the IMbrave050 study has created a precedent for the study of adjuvant drug therapy after liver cancer surgery.
2. Systemic drug therapy
Even though the clinical research of drugs for the treatment of liver cancer has been reported frequently in recent years, and the combination of local interventional therapy + systemic drug therapy has achieved unprecedented efficacy, the burden of liver cancer on the mainland and even the world is still heavy. Therefore, the research on exploring new drugs, new models and new protocols has been continuous, and extensive benefits, lower toxicity and less economic burden have always been the common goals pursued by the majority of experts and scholars.
The results of a phase III clinical trial published in Lancet in 2023 showed that camrelizumab combined with apatinib bisorafenib in patients with unresectable liver cancer showed significant advantages in improving PFS time and OS time, with a median PFS time of 5.6 months, a median OS time of 22.1 months, and a 1-year OS rate of 76.5% in patients with camrelizumab plus apatinib It has a good safety profile and is expected to open a new paradigm of first-line drug therapy for advanced liver cancer [19].
In addition, clinical studies of targeted therapies and immunotherapy in combination with immunosensitizing drugs are emerging, among which tirellumab is a human-derived anti-TIGIT (inhibitory receptor expressed on lymphocytes) monoclonal antibody that may enhance its anti-tumor effects when combined with other immunotherapies such as programmed cell death ligand 1 (PD-L1) inhibitors. Some of the results of the MORPHEUS-Liver study were presented at the 2023 ASCO Annual Meeting [20]. The Phase I.b/III study was designed to evaluate the efficacy and safety of tirellumab in combination with atezolizumab plus bevacizumab in the treatment of unresectable liver cancer, and the results showed that the addition of tirellumab to atezolizumab and bevacizumab resulted in higher ORR and longer PFS, and no new safety signals were observed. Triple drug therapy may become a new option for first-line treatment of advanced liver cancer.
In terms of immunotherapy, the four-year OS rate of the phase III HIMALAYA study was updated at the 2023 ESMO Asia Annual Meeting [21]. The results of this study showed that the 4-year OS rate of tramelimumab (cytotoxic T lymphocyte-associated antigen 1 inhibitor) combined with durvalumab (PD-L1 inhibitor) was higher than that of sorafenib (15.1%), and the 3-year OS rate of the disease control population was close to 45%, and the 4-year OS rate was close to 36%. An evaluation of baseline data from long-term survivors (≥ 36 months) found that the long-term survivors in the STRIDE (single-dose high-initiation tesimumab + durvalumab) group were basically consistent with the overall population in terms of demographic characteristics, clinical characteristics, subsequent treatment, and trimelimumab rechallenge, indicating that the long-term survivors were not from any particular subgroup, suggesting that different patients with unresectable HCC may benefit from STRIDE in long-term survival, and no new serious adverse events were observed. The HIMALAYA study, which demonstrated unprecedented 3- and 4-year OS rates in the Phase III study and the longest follow-up time to date in the Phase III unresectable HCC study, further strengthened the clinical understanding of the efficacy and safety of the dual-immunization regimen, and was approved by the U.S. Food and Drug Administration in October 2022 for the first-line treatment of advanced liver cancer, becoming the first dual-immunotherapy regimen approved for the first-line treatment of liver cancer.
In addition, cadonilimab is the first domestic bispecific antibody drug approved for marketing targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4. Results from a Phase I.b, II, single-arm trial (COMPASSION-08) evaluating the efficacy and safety of cadonilimab in combination with lenvatinib in the first-line treatment of advanced liver cancer (COMPASSION-08) were published in Frontiers in Immunology in 2023 [22]. The study enrolled 59 patients who were treated with cadonilimab plus lenvatinib at 6 mg/kg every 2 weeks (Cohort A, 31 patients) or cadonilimab plus lenvatinib at 15 mg/kg every 3 weeks (Cohort B, 28 patients), with a median follow-up of 27.4 months, with an ORR of 35.5% for Cohort A and 35.7% for Cohort B. The median PFS time in Cohorts A and Cohort B was 8.6 months and 9.8 months, respectively, and the median OS time in Cohort A was 27.1 months, while Cohort B did not reach it, with 66.1% of patients ≥ grade 3 treatment-related adverse events and 39.0% of patients experiencing serious treatment-related adverse events. The above results suggest that cadonilimab combined with lenvatinib has good anti-tumor activity and acceptable safety profile in the first-line treatment of advanced liver cancer, and this new combination is also worthy of further exploration.
In recent years, the application of immunotherapy for liver cancer has improved the therapeutic effect of liver cancer, and after several years of efforts, great progress has been made in dual-drug combination therapy with immunotherapy as the core, but the efficacy seems to be about to reach the "ceiling". The addition of tiremlumab has brought the drug treatment of liver cancer into the era of three-drug combination, and whether there will be new progress still needs to be further explored. Recently, domestic scholars have used chemotherapy combined with targeted therapy and immunotherapy for liver cancer, and small sample studies have achieved certain efficacy, which may also be a new direction of drug treatment for liver cancer.
3. Multidisciplinary combined therapy
3.1 Ablation combined with drug therapy
A prospective phase II clinical trial (NCT04652440) conducted by the team of Professor Chen Minshan from the Sun Yat-sen University Cancer Center to evaluate the safety, tolerability, and preliminary efficacy of percutaneous thermal ablation in combination with tislelizumab in patients with BCLC stage A and B liver cancer was presented at the 2023 ESMO Asia Annual Meeting [23]. The study included 30 treatment-naïve or relapsed patients with 1 or 2 sizes of 2~5 HCC patients with CM lesions were divided into two stages: 6 patients were included in the first stage for dose-limiting toxicity observation, and only when less than 2 patients had dose-limiting toxicity will they enter the second stage and the other 24 patients will be included; the enrolled patients were intravenously injected with the first course of tislelizumab 1 day before percutaneous thermal ablation, and infusion once every 3 weeks for a total of 4 courses; no dose-limiting toxicity was observed in the first 6 patients, and a total of 26 enrolled patients completed treatment and received regular follow-up; the most common adverse events were increased alanine aminotransferase (15 cases) and aspartate aminotransferase (19 cases) on the first day after ablationGrade 1 and 2 immune-related adverse events occurred in 10 patients, with rash (8 patients), pruritus (5 patients), and anorexia (4 patients), and no grade 3 immune-related adverse events observed. Percutaneous thermal ablation combined with tislelizumab has demonstrated acceptable safety and tolerability, and efficacy evaluations will be announced in the future.
3.2 Interventional combination drug therapy
The interim results of the prospective single-arm phase II trial (DurHope study) in patients with advanced liver cancer with severe portal vein cancer thrombosis (Vp3, Vp4) led by Professor Zhao Ming of Sun Yat-sen University Cancer Center presented interim results in a poster at the 2023 ESMO Annual Meeting [24]. The study showed not only a favorable safety profile, but also the expected clinical effect: ORR of 47.4% (9/19), partial response in 8 patients, complete response in 1 patient, median PFS time of 5.5 months, and a multicenter, Results from randomized controlled trials have shown that the addition of HAIC significantly improves ORR and significantly prolongs OS in patients receiving second-line therapy compared with regorafenib in combination with a PD-1 inhibitor [25].
The EMERALD-1 study (NCT 03778957) is a randomized, double-blind, placebo-controlled, multicenter, phase III study to evaluate the efficacy and safety of transcanduit arterial chemoembolization (TACE) in combination with durvalumab ± bevacizumab in patients with intermediate-stage unresectable liver cancer [26]. The study spanned 18 countries and regions, and 616 patients were enrolled and randomly divided into three groups on a 1:1:1 basis: group A was treated with TACE plus durvalumab, and durvalumab plus placebo was given after the last TACE, group B was treated with TACE plus durvalumab and duvalumab after the last TACE, and group C was treated with TACE plus placebo, and placebo plus placebo after the last TACE, OS time as a secondary endpoint requires a longer follow-up time. The EMERALD-1 study is the first large-scale Phase III clinical study to explore immunotherapy and macromolecular anti-angiogenic targeted drugs in combination with TACE in the treatment of unresectable advanced liver cancer with positive results, providing high-level evidence-based medical evidence for clinical practice, and we look forward to the release of more research data to make this new combination regimen benefit more liver cancer patients.
3.3 Radiotherapy combined with drug therapy
Results from a prospective study published in Clinical Cancer Research in 2023 showed that stereotactic radiosurgery combined with camrelizumab and apatinib had good efficacy and safety in the first-line treatment of liver cancer with portal vein cancer [27]. Another multicenter prospective study, published in Frontiers in Immunology, showed that intensity-modulated radiotherapy combined with atezolizumab plus bevacizumab resulted in higher response rates in patients with liver cancer and portal vein cancer [28]. A growing body of evidence suggests that radiotherapy is effective in the treatment of liver cancer with portal vein thrombosis, especially in combination with systemic drug therapy, which may add new options to standard therapy.
For advanced liver cancer, the control of intrahepatic tumor treatment is still the most important, and local treatment (including interventional therapy, ablation therapy, and radiotherapy) is rapid and effective, so even if extrahepatic metastases require drug therapy, local treatment of liver cancer is still essential. Based on local therapy + systemic therapy as the treatment mode of unresectable advanced liver cancer, mainland scholars have carried out a large number of clinical treatment studies and explorations, and have discovered many effective and feasible treatment options for the treatment of advanced liver cancer, which has confirmed the significance of multidisciplinary treatment of liver cancer.
4. Summary
The rapid development of conversion therapy and perioperative therapy in recent years has brought good news to the long-term survival of liver cancer patients, but there are many treatment methods for liver cancer, and the treatment modes for liver cancer patients at different stages are different, and different treatment modes involve cross-disciplinary collaboration. From the period of immune monotherapy to the new progress of targeted therapy and immunotherapy combined with local therapy and immunosensitizing drugs, the diversity of comprehensive treatment concepts for liver cancer has been highlighted. In the treatment selection of intermediate and advanced liver cancer, it is necessary to comprehensively evaluate the patient's condition and individual differences, consider the balance of multiple disciplines and methods, and concentrate on solving the problem of poor efficacy of intermediate and advanced liver cancer. At the same time, through clinical trial research, we will further explore the potential beneficiary groups, improve the treatment effect, improve the prognosis and quality of life of patients, and promote the effective improvement of the clinical diagnosis and treatment level of liver cancer in mainland China.
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