Authors:Chinese Expert Consensus Collaborative Group for Neoadjuvant Therapy for Liver Cancer, Digestive Surgery Committee of Chinese Research Hospital Association, Liver Cancer Committee of Chinese Anti-Cancer Association.
Article source: Chinese Journal of Surgery, 2023, 61(12)
summary
Neoadjuvant therapy is an effective treatment to reduce postoperative recurrence and prolong the survival of patients, but there is no recognized effective treatment for neoadjuvant therapy for liver cancer. In recent years, with the progress of systemic anti-tumor drugs represented by targeted and immune checkpoint inhibitors, as well as the improvement of local treatment methods for liver cancer, these treatment regimens have been initially and effectively explored in the field of neoadjuvant therapy for liver cancer. Under the leadership of the Digestive Surgery Committee of the Chinese Association of Research Hospitals and the Liver Cancer Professional Committee of the Chinese Anti-Cancer Association, the Chinese Expert Consensus on Neoadjuvant Therapy for Liver Cancer (2023 Edition) has been formulated after many discussions and revisions, aiming to provide targeted guidance for preoperative liver cancer treatment decisions based on the characteristics of liver cancer diagnosis and treatment in China, and further standardize the implementation path of neoadjuvant therapy.
Primary liver cancer is the sixth most common cancer and the third leading cause of cancer death in the world, with about 900,000 new cases of primary liver cancer and about 830,000 new primary liver cancer-related deaths in 2020. Among them, there were about 410,000 new cases of primary liver cancer in China (45.3%) and about 390,000 new deaths (47.1%), ranking first in the world [1]. Hepatocellular carcinoma (HCC) is the most common pathological type of primary liver cancer, accounting for about 90% of primary liver cancer cases in mainland China [2]. Surgical treatment is the treatment of choice for patients with resectable liver cancer. In recent years, the overall survival rate of patients with liver cancer after hepatectomy has increased to 60.0%, but the recurrence rate of liver cancer after surgery is high, especially in patients with resectable liver cancer stage II.b and III.a in China liver cancer staging (CNLC), whose one-year recurrence rate is more than 55%, and the recurrence rate of patients with stage I.b and II.a liver cancer has reached 32.4% and 45.7% [3]. Reducing the risk of postoperative recurrence and prolonging the survival time of patients are the main goals of neoadjuvant therapy for liver cancer, but there is no accepted standardized treatment paradigm. In order to further clarify the concept of neoadjuvant therapy, grasp the indications for treatment, clarify the timing of surgery, and select the best drug regimen, the First Affiliated Hospital of Nanjing Medical University has carried out a series of clinical and basic studies on neoadjuvant therapy for liver cancer since 2019 [4, 5, 6], on this basis, the Digestive Surgery Committee of the Chinese Research Hospital Association and the Liver Cancer Professional Committee of the Chinese Anti-Cancer Association organized relevant experts to launch the Chinese Expert Consensus on Neoadjuvant Therapy for Liver Cancer (2023 Edition) in March 2023 of the development of the work. The purpose of this consensus is to provide guiding suggestions for preoperative neoadjuvant therapy decision-making based on the characteristics of liver cancer diagnosis and treatment in China, and to further standardize the implementation path of neoadjuvant therapy. The evaluation of evidence-based medicine in this consensus refers to the grading of recommendations, assessment, development and evaluation (GRADE) classification [7] and the Oxford Evidence-Based Medicine Centre Classification 2011 (Table 1), the strength of expert recommendations is mainly based on the GRADE guidelines for the grading of recommendations [8], and the grading of recommendations is partially modified in combination with the grading scheme of the ASCO guidelines [9]. In this paper, recommendations are divided into three levels: A (strong recommendation), B (moderate recommendation), and C (weak recommendation) (Table 2). Recommendation strength A indicates that the panel has strong confidence that the recommendation reflects best clinical practice and that the recommendation should be adopted by all target populations. Recommendation strength B indicates that the expert group has a moderate level of confidence in the recommendation reflecting best clinical practice, and that the majority of the target population should adopt the recommendation and that the implementation should take into account the shared decision between the provider and the patient. Recommendation strength C indicates that the recommendation reflects some confidence in best clinical practice and should be conditionally applied to the target population, emphasizing doctor-patient co-decision-making based on the patient's value preference.
1. Consensus-setting methodology
(1) Literature search
The foreign language databases searched included PubMed and Web of Science, and the Chinese databases included CNKI and Wanfang Database. The main free words and subject headings included liver cancer, surgery, neoadjuvant therapy, all original studies involving the effects of preoperative neoadjuvant combined surgery on the treatment of liver cancer, browsing the reference list and searching for studies that may have been missed. The search formula for foreign language databases is ("hepatocellular carcinoma" OR "HCC" OR "liver cancer" OR "primary liver carcinoma")AND("liver resection" OR "surgical resection" OR "hepatectomy" OR"resectable")AND(" neoadjuvant" OR "perioperative"[Title]OR "preoperative"[Title]), the search formula in Chinese is ("liver cancer" + "primary liver cancer" + "hepatocellular carcinoma")*("liver resection" + "surgery")*("neoadjuvant"). The last search was conducted in August 2023.
(2) Literature selection criteria
(1) the literature types were systematic reviews or meta-analysis, randomized controlled studies, non-randomized controlled studies, cohort studies, retrospective analysis of registries databases, and abstracts of high-quality randomized controlled trials; (2) the study population was a well-diagnosed and initially resectable hepatocellular carcinoma; (3) neoadjuvant therapy regimens included transarterial chemoembolization (TACE), Hepatic arterial infusion chemotherapy (HAIC), radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc., with surgery alone as the control group, and high-quality single-arm neoadjuvant therapy clinical trials without control were also included;(4) The study endpoints were clearly defined, including but not limited to pathological endpoints, imaging tumor assessment endpoints, survival outcomes, etc. The languages are Chinese and English.
(3) Quality control
All searches were performed independently by two investigators. After aggregating the data, the dissenting articles are discussed, and the authors of the articles are contacted for discussion if necessary. In addition, experts in liver surgery, interventional surgery, medical oncology, radiotherapy, imaging, pathology and other related fields were consulted to discuss and summarize the opinions of different experts.
2. The concept, applicable population, and treatment cycle of neoadjuvant therapy for liver cancer
Neoadjuvant therapy for liver cancer refers to the treatment of patients with liver cancer who are technically resectable (can achieve R0 resection and the remaining liver volume is sufficient), Child-Pugh grade A and some B, and are accompanied by high-risk recurrence factors, to be given systematic treatment and/or local treatment (interventional or radiotherapy) before surgery, with the aim of reducing the risk of local recurrence and systemic metastasis through preoperative intervention, shrinking the tumor, improving the R0 resection rate, and eliminating subclinical lesions and distant metastases. At the same time, the sensitivity of anti-tumor regimens was tested to provide necessary information for the selection of postoperative adjuvant treatment regimens.
Recommendation 1: Neoadjuvant therapy for HCC refers to systemic therapy and/or local treatment measures for patients with initially resectable HCC with high-risk recurrence factors (expected to achieve R0 resection, adequate residual liver volume, Child-Pugh class A and some B) to reduce the risk of recurrence and metastasis and improve survival (level of evidence 2, strength of recommendation A).
The main goal of neoadjuvant therapy is to reduce the risk of recurrence and metastasis and improve patient survival. Combined with the recommendations of the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer [10], it is recommended that patients with initial radical resection in CNLC stage I.b~II.a with sufficient residual liver volume and risk factors for postoperative recurrence should be enrolled in the clinical trial of neoadjuvant therapy after the multidisciplinary therapy (MDT) team discusses and confirms the high-risk recurrence. The risk factors for recurrence after CNLCI.b and II.a are mainly based on preoperative imaging features (incomplete tumor capsule and tumor adjacent blood vessels, etc.), with reference to alpha-fetoprotein [11, 12] and abnormal prothrombin levels [13], and can also be combined with hepatitis B viral load, end-stage liver disease model score, and preoperative imaging features to construct a postoperative recurrence prediction model [11,14]. Patients with resectable CNLC stage II.b and III.a have a recurrence rate of more than 55% at one year after surgery [3], and are also the target population of neoadjuvant therapy, and it is recommended to join the clinical trial of neoadjuvant therapy or undergo neoadjuvant therapy after discussion by the MDT team. In addition, it is important to emphasize that there is currently no evidence that patients with stage I.a can benefit from neoadjuvant therapy, and that patients may also lose the opportunity to undergo surgery due to the toxic side effects of neoadjuvant therapy and the prolonged duration of surgery, so neoadjuvant therapy is not recommended for patients with stage I.a.
Recommendation 2: The target population of neoadjuvant therapy for liver cancer includes: (1) patients with resectable CNLC I.b~II.a with risk factors for recurrence, and the risk factors for preoperative recurrence include incomplete tumor capsule, tumor adjacent to blood vessels, alpha-fetoprotein > 400 μg/L, or high recurrence population defined based on preoperative radiomics model, it is recommended that the above patients join neoadjuvant clinical trials; For patients with stage III.a, neoadjuvant therapy is recommended to be enrolled in a neoadjuvant clinical trial or discussed by the MDT team (level of evidence 2, strength of recommendation A).
At present, it is accepted that the clinical diagnosis of liver cancer is mainly based on imaging examination combined with serological examination (non-invasive diagnostic criteria). However, in recent years, the American College of Hepatology has begun to encourage patients receiving neoadjuvant therapy to undergo liver biopsy before starting treatment, which can obtain pathologic information about the tumor and liver, including tumor histological type, degree of differentiation, tumor capsule formation, degree of lymphocyte and cell subtype infiltration, type and degree of lymph node tertiary structure formation, and grading and staging of hepatitis and cirrhosis, and compare histopathological and molecular biological changes before and after neoadjuvant therapy [15]. Molecular pathology analysis assesses clonal origin, gene variation, drug targets, and biological behavior, and is used to predict patient outcomes, among other things. However, due to the limitations of the specimens obtained from the liver biopsy and the possible possibility of liver cancer dissemination and hemorrhage, it is necessary to consider a variety of factors when deciding whether to perform a needle biopsy and ensure the patient's full informed consent.
Recommendation 3: For patients receiving neoadjuvant therapy, liver biopsy can be considered before treatment to roughly understand the patient's local immune microenvironment status of liver cancer before surgery, and provide the necessary pathological reference for clinical design of neoadjuvant treatment regimen and evaluation of possible treatment response (level of evidence 3, strength of recommendation C).
During neoadjuvant therapy, patients may lose the opportunity for surgery due to disease progression or serious adverse effects after treatment. Therefore, it is important to grasp the preoperative neoadjuvant therapy cycle, and ensure that the treatment goal is achieved within a limited time frame to reduce the failure rate of neoadjuvant therapy. The cycle of neoadjuvant therapy for liver cancer is generally recommended to be 6~12 weeks (up to 16 weeks), so as to strive for surgery as soon as possible after the treatment goal is achieved (regardless of whether the lesion shrinks or not).
The treatment plan can be individualized according to the general condition of the patient and the reserve capacity of liver function, and in principle, the treatment method with less impact on liver function should be adopted to not affect the subsequent surgical treatment. The use of small molecule tyrosine kinase inhibitors (TKIs) in the neoadjuvant treatment of liver cancer does not increase the incidence of postoperative complications [16, 17]. Some investigators have recommended discontinuation of TKIs for more than one week prior to surgery [18]. For patients receiving neoadjuvant regimens with immune checkpoint inhibitors (ICIs), surgery is recommended more than four weeks after the last dose [19, 20]. Patients with HCC who are on ICIs require liver function tests such as aminotransferases prior to surgery and, if necessary, liver biopsy to assess for the presence of immune hepatitis, which may increase the risk of perioperative mortality [21]. Based on the experience of hepatic resection for colorectal cancer liver metastases, bevacizumab needs to be discontinued for more than six weeks prior to surgery [22], and should be used with caution during neoadjuvant therapy. Surgical treatment four weeks after the end of TACE has been shown to have no significant effect on perioperative morbidity and mortality [23, 24]. In addition, liver resection four weeks after the end of embolism for portal vein trunk cancer can minimize the incidence of complications such as intraoperative bleeding and postoperative liver failure [25].
Recommendation 4: The treatment cycle of neoadjuvant therapy for liver cancer is 6~12 weeks, and the longest is not more than 16 weeks. Regardless of whether the lesion has shrunk or not, surgery should be performed as soon as the goal of treatment is achieved. Discontinuation of small molecule TKIs for one week prior to surgery, discontinuation of ICIs for four weeks is recommended, and the recommended time between surgery and last TACE or radiotherapy is four weeks (level of evidence 2, strength B recommended).
3. The necessity of MDT team in neoadjuvant therapy for liver cancer
Liver cancer is highly heterogeneous, and the choice of treatment is complex. The MDT model is a diagnosis and treatment model in which a diagnosis is made and a treatment plan is developed after discussion among professionals in multiple related disciplines in order to achieve the best possible outcome [26]. In the course of neoadjuvant therapy for liver cancer, MDT is essential. MDT can be discussed to provide individualized and comprehensive diagnosis and treatment services for patients with liver cancer, thereby improving treatment outcomes [27, 28]. It is suggested that the MDT discussion of neoadjuvant therapy for liver cancer should be led by liver surgeons, with the participation of physicians from oncology, interventional medicine, imaging, radiotherapy, hepatology, pathology and other departments. The composition of the MDT team should be relatively fixed. MDT discussion should provide an adequate assessment of whether the patient would benefit from neoadjuvant therapy. In medical units where conditions permit, the MDT team should evaluate whether the patient can participate in the relevant clinical trials of neoadjuvant therapy for liver cancer. In the process of neoadjuvant therapy, the specific treatment regimen to be used, the timing of surgery after treatment, and the management of treatment-related adverse effects all require repeated discussion and full communication between multiple disciplines [29].
Recommendation 5: The MDT team is necessary in the neoadjuvant treatment of patients with liver cancer, and the discussion suggests that the liver surgeon should lead the discussion, with the participation of physicians from oncology, interventional medicine, radiology, radiotherapy, hepatology, pathology and other departments, comprehensively evaluate whether the patient can benefit from neoadjuvant therapy, and select the appropriate neoadjuvant treatment plan for the patient according to the principle of individualization (level of evidence 2, strength of recommendation A).
4. Neoadjuvant therapy for liver cancer
(1) Interventional treatment
TACE therapy is the earliest exploration direction of neoadjuvant therapy for liver cancer. In 2009, Zhou et al. [30] reported a prospective study in which 108 patients with resectable liver cancer with a maximum tumor diameter of ≥5 cm were randomly assigned to the preoperative TACE group and the preoperative untreated group. In 2016, Zhang et al. [31] reported the results of a prospective non-randomized controlled study showing that preoperative TACE treatment can improve the survival of patients with resectable liver cancer and portal vein cancer thrombosis (especially those with portal vein cancer type I and type II), but the results of prospective randomized controlled studies still need to be confirmed.
In 2023, Zhu et al. [32] published the results of a national multicenter real-world study (CHANCE001) showing that compared with TACE treatment, TACE combined with PD-1/PD-L1 inhibitors and targeted drugs can improve progression free survival (PFS), overall survival (OS) and objective response rate (objective) in patients with advanced liver cancer response rate (ORR), with a median PFS of 9.5 months, a median OS of 19.2 months, and an ORR of 60.1% in the combination treatment group. Guo et al. [33] conducted a prospective single-arm phase II clinical study to investigate the efficacy of TACE in combination with PD-1 inhibitors in patients with stage A and B liver cancer that exceeded the Milan criteria for Barcelona Clinic Liver Cancer (BCLC), including some patients with initial unresectable ORR of 62% and complete pathological response, CPR) rate of 14%, preliminary results suggest that TACE combined with PD-1 inhibitors has potential advantages in improving ORR and CPR rates, but whether TACE combined with target-immune therapy can reduce the postoperative recurrence rate of resectable liver cancer and improve the prognosis of high-risk patients still needs to be further verified by high-evidence clinical trials. In addition, how to standardize the use of TACE therapy and how to combine TACE treatment with other treatment methods are important research directions in the future, and also have potential application prospects. However, due to the limited level of evidence, more clinical trial results are needed to further clarify its efficacy and safety.
Recommendation 6: TACE alone is not recommended as a neoadjuvant treatment for HCC, and TACE is recommended in combination with targeted and/or immunotherapy as an option for neoadjuvant therapy (level of evidence 2, strength of recommendation B).
HAIC treatment can lead to more survival benefits and lower recurrence rates in patients with resectable liver cancer. In 2023, Prof. Rongping Guo's team reported in the form of a conference paper the effect of HAIC in the treatment of HCLC stage A and B HCC with ultra-Milan standard [34], and the results showed that HAIC treatment improved PFS and OS, but not RFS. In another retrospective study comparing patients with resectable BCLC stage B and C HCC who received portal infusion chemotherapy or HAIC, the HAIC group had better event-free survival than adjuvant portal infusion chemotherapy [35]. However, the optimal beneficiaries of HAIC treatment, as well as the type, dose, duration and combination of perfusion drugs with systemic therapy still need to be further clarified by more clinical trials.
Recommendation 7: The use of HAIC as a neoadjuvant therapy for liver cancer may reduce the rate of postoperative recurrence and improve patient outcomes (level of evidence 3, strength of recommendation B).
(2) Radiotherapy
Radiotherapy has also made important progress in the study of resectable liver cancer. In a 2019 multicenter randomized controlled study comparing neoadjuvant three-dimensional conformal radiotherapy with hepatectomy alone in patients with HCC with portal vein thrombosis showed that radiotherapy reduced HCC-related mortality and recurrence compared with surgery alone [36]. In 2022, a single-arm phase II clinical trial included 38 patients with central liver cancer, all of whom received intensity-modulated radiotherapy before surgery, and the 1-, 3-, and 5-year OS rates were 94.6%, 75.4%, and 69.1%, respectively, and the 1-, 3-, and 5-year tumor-free survival rates were 70.3%, 54.1%, and 41.0%, respectively [37], and the incidence of radiotherapy-related grade 3 adverse reactions was only 7.9%, suggesting that radiotherapy was emphasized to be safe and effective for patients with central HCC before surgery.
Recommendation 8: Neoadjuvant precision radiotherapy may reduce postoperative recurrence and improve survival in patients with hepatocellular carcinoma with portal vein thrombosis (level of evidence 2, strength of recommendation B), and neoadjuvant intensity-modulated radiotherapy may improve the prognosis of patients with central liver cancer (level of evidence 3, strength of recommendation C)
(3) Targeted and immunotherapy
At present, targeted therapy drugs for liver cancer mainly include TKIs (sorafenib, lenvatinib, donafenib, regorafenib, apatinib, etc.) and anti-vascular endothelial growth factor antibodies (bevacizumab and its analogues), but there are no studies on targeted neoadjuvant therapy alone. In recent years, ICIs have made breakthroughs in the treatment of advanced liver cancer, providing new treatment options for neoadjuvant therapy for patients with resectable liver cancer [38, 39]. In 2022, the results of three clinical trial studies of neoadjuvant therapy for liver cancer with ICI as the core were officially released, bringing new treatment options to patients with resectable liver cancer.
The pathology results of the neoadjuvant clinical trial of the PD-1 inhibitor camrelizumab combined with apatinib showed that 5.9% of patients achieved CPR and 17.6% achieved major pathological response (MPR) (necrosis rate ≥ 90%), and the one-year RFS rate of patients was 53.85%, the RFS rate of patients with CPR was higher than that of patients with non-CPR, and the RFS rate of patients with single lesions was higher than that of patients with multiple lesions [4]. Clinical studies of the PD-1 inhibitor cemiplimab in the neoadjuvant setting showed that 35 percent of patients had a tumor necrosis rate of 50 percent or more, and 65 percent of patients had a tumor necrosis rate of less than 30 percent [40]. In a randomized controlled trial of the PD-1 inhibitor nivolumab, 27 of the 30 patients were randomly assigned to nivolumab monotherapy (13 to nivolumab monotherapy and 14 to nivolumab plus ipilimumab) [19], with a median PFS of 9.4 months and 19.53 months for 25 patients who completed complete treatment.
On the basis of satisfactory results in three clinical studies of neoadjuvant therapy with exploratory immunodrugs, Academician Wang Xuehao's team selected 129 patients with direct surgical resection of CNLC stage II.b and III.a liver cancer who were admitted at the same time from the prospective liver cancer cohort as a conventional control group on the basis of the single-arm study of camrelizumab combined with apatinib, and analyzed the efficacy and safety of immune neoadjuvant therapy for liver cancer. The one-year recurrence rate was 42.9 percent in the neoadjuvant group and 64.0 percent in the conventional control group (P<0.05), but there was no significant difference in surgical safety between the two groups [41].
Zhao et al. [42] conducted a comprehensive analysis of 9 clinical studies on neoadjuvant immunotherapy in liver cancer including the above three published clinical trials, and found that the CPR rate in the neoadjuvant therapy group was 12.9% (95%CI: 6.7%~19.1%), and the MPR rate was 27.3% (95%CI: 15.1%~39.4%), suggesting that there was a correlation between neoadjuvant immunotherapy and better clinical prognosis (CPR: OR=0.17, P<0.01；MPR：OR=0.38，P=0.001）。 Although no specific ICI regimen with significant advantages was found in subgroup analyses, patients with resectable HCC were well tolerated with neoadjuvant ICI therapy and showed significant results at the histopathological level.
Recommendation 9: Neoadjuvant immunotherapy may improve the prognosis and CPR rate of patients with HCC, and recommend that patients with HCC who meet the criteria be enrolled in clinical trials of neoadjuvant immunotherapy (level of evidence 2, strength of recommendation B).
5. Evaluation indicators of the effectiveness of neoadjuvant therapy for liver cancer
Commonly used indicators in clinical trials of neoadjuvant therapy for liver cancer include tumor ORR, pathological evaluation indicators (MPR, CPR), event-free survival (EFS), time to tumour progression (TTP), RFS, time to tumour recurrence (TTR) and OS. For the imaging monitoring and analysis of liver cancer lesions, dynamic contrast-enhanced CT and MRI examinations have high clinical applicability, among which MRI examinations have a higher detection rate for small lesions [43], especially Gd-EOB-DTPA-enhanced MRI examinations provide a more accurate evaluation method for multiple small lesions. Therefore, for patients with liver cancer receiving neoadjuvant therapy, dynamic contrast MRI is recommended as a priority for imaging evaluation. Imaging is usually done before surgery after neoadjuvant therapy, and radiographers evaluate tumors based on response evaluation criteria in solid tumours (RECIST) 1.1 and/or modified RECIST to assess tumors and calculate ORR to reflect recent antitumor activity, however, because the duration of neoadjuvant therapy is not long, and the ORR is often less than 30% The correlation with OS is not high, so ORR should not be used as the primary endpoint.
After the completion of neoadjuvant therapy and surgery, pathologists need to focus on the pathological indications such as the degree of necrosis of tumor lesions, the pathological grade of microvascular invasion, and the tertiary structure of lymph, so as to evaluate the effect of immune neoadjuvant therapy for tumors. MPR can be calculated by dividing the estimated size of the residual active tumor by the size of the tumor bed, and it is recommended that the residual active tumor ≤ 30 percent (ie, necrosis rate ≥ 70 percent) be considered MPR, and has been used in two clinical trials of neoadjuvant therapy for liver cancer [19,40]. In addition, in view of the lack of experience in pathology in judging the effect of neoadjuvant therapy for liver cancer, it can also be reported in the form of ≤10%, > 10%~30%, >30%~50%, and >50%, so as to accumulate more data to guide the establishment of the cut-off value of MPR in the later stage. CPR is defined as the absence of any active tumor cells in HE-stained sections after complete evaluation of all resected samples, including the sampled regional lymph nodes [44]. Different definitions of necrosis rates can lead to differences in MPR results, which have been reported in multiple studies [4,19,40]. RFS is used only in patients undergoing curative surgery and is defined as the time from the start of surgery to tumor recurrence or death from any cause, and EFS is the time from randomization to the following events: disease progression excluding surgery, local recurrence, distant metastases, or death from any cause. In contrast to RFS, TTR does not include fatal events. In contrast to RFS, EFS includes cases in which neoadjuvant therapy is initiated but no surgery or surgery is not scheduled. OS is defined as the time from randomization to death from any cause.
According to the case report of the First Affiliated Hospital of Nanjing Medical University, for high-risk CNLC stage I.b~III.a patients, 50% of recurrence occurred 12~18 months after surgery, and 50% of deaths were observed at 24~60 months[3]. Therefore, EFS or RFS is recommended as the primary efficacy endpoint, and ORR, TTP, TTR, OS, MPR, and CPR as secondary efficacy measures. OS is most commonly used as the primary endpoint in registry trials of advanced HCC [15,45], but patients who have undergone surgery have a longer survival time and receive subsequent therapy after recurrence can affect OS. However, we still recommend that follow-up to five years postoperatively can be continued from the original trial to assess the long-term efficacy of neoadjuvant therapy by observing OS. In addition, whether MPR can be used as a surrogate endpoint for neoadjuvant therapy still needs to be further explored.
Recommendation 10: The primary efficacy measures of neoadjuvant therapy for HCC are RFS or EFS, and the secondary efficacy measures include MPR, ORR, TTP, TTR, and OS (level of evidence 2, strength of recommendation A). It is recommended that the MPR of neoadjuvant therapy for HCC be defined as the proportion of residual viable tumour cells ≤30% (level of evidence 3, strength of recommendation B).
6. Adverse reactions of neoadjuvant therapy for liver cancer
(1) Adverse reactions of neoadjuvant interventional therapy and radiotherapy
TACE has the advantages of less trauma, low risk, lower cost, and better patient tolerance, and complications with a high incidence include post-embolic syndrome such as fever, abdominal pain, vomiting, etc., some rare complications include liver abscess, heart damage, etc., and some serious complications such as liver failure, gastrointestinal bleeding, liver rupture, etc., can even be life-threatening. It is essential to identify and properly manage these complications in a timely manner. Among them, liver and kidney function impairment is a relatively common adverse reaction of TACE in the treatment of liver cancer [46], and such patients should be routinely evaluated for liver and kidney function and coagulation function before surgery, given intravenous infusion of hepatoprotective drugs after surgery, and strengthen hydration and alkalinization of urine according to kidney function and use drugs to protect kidney function, promote the recovery of liver and kidney function, and reduce the potential risk caused by liver and kidney dysfunction. At the same time, superselective intubation should be carried out as much as possible during surgery, the use of larger doses of chemotherapy drugs should be avoided, and the amount of iodized oil should be strictly controlled.
Adverse effects of external beam radiotherapy include gastrointestinal symptoms, bone marrow suppression, and peripheral neurotoxicity [47], which are generally tolerated by patients and largely resolved after the end of radiotherapy or symptomatic management. The main radioactive effects of internal radiotherapy in China are 125 I, and the adverse reactions of internal radiotherapy mainly include radiation liver injury and radiation pneumonitis, while radiation gastrointestinal injury and gallbladder complications are rare [48]. In addition, radiotherapy may increase the difficulty of surgery and the risk of related complications due to the damage of liver tissue and hilar blood vessels, so more precise radiotherapy and more delicate intraoperative surgical operations are required. However, the impact of neoadjuvant radiotherapy on surgical safety needs to be confirmed by more clinical trial data.
(2) Adverse reactions of neoadjuvant targeting and immunotherapy
Common adverse effects of antivascular-targeted drugs, such as sorafenib, lenvatinib, and donafenib, include hypertension, proteinuria, rash (hand-foot syndrome), hypothyroidism, and diarrhea [49]. ICIs may lead to immune-related adverse events (irAEs) while activating immune function in patients with liver cancer, including dermatotoxicity, enteritis, endocrine toxicity, hepatitis, and pneumonia [25]. The incidence of irAE in liver cancer is comparable to that of other tumors, but liver cancer patients often have systemic manifestations due to their own liver problems, which leads to the superposition or interaction of extrahepatic organ dysfunction and immune-related adverse reactions. In addition, when targeted drugs are combined with ICIs, there may be superimposed adverse reactions, such as abnormal liver function, rash, diarrhea, etc., which require further differential diagnosis and correlation judgment.
Common adverse effects of three clinical trials of neoadjuvant immunotherapy include elevated aminotransferases, anemia, constipation, fatigue, hypothyroidism, elevated lipase, nausea, decreased platelet count, pruritus, maculopapular rash, and hypertension. Overall, the adverse reactions of dual immunization or immunization combined TKI are higher than those of ICI monotherapy, and timely diagnosis and treatment of adverse reactions in targeted therapy and immunotherapy have an important impact on the overall neoadjuvant therapy strategy and patient compliance of patients with liver cancer.
The risk of bleeding should be paid attention to in the process of neoadjuvant therapy, especially gastrointestinal bleeding, because patients with liver cancer are more likely to have liver cirrhosis and portal hypertension, and gastrointestinal bleeding during neoadjuvant therapy may lead to the loss of surgery or even death, especially in the neoadjuvant treatment regimen in combination with anti-angiogenic targeted drugs, which will lead to a higher risk of gastrointestinal bleeding. The effect of atezolizumab combined with bevacizumab and targeted drugs such as donafenib, apatinib, and anlotinib on complications related to portal hypertension, such as gastrointestinal bleeding, has been reported in relevant clinical trials. The results of a meta-analysis of 50 randomized clinical trials showed that TKIs including lenvatinib, apatinib, and sorafenib were associated with an increased risk of bleeding (OR=1.79, 95%CI: 1.50~2.13, P<0.01）［50］。 In the IMbrave150 trial, atezolizumab plus bevacizumab was associated with higher bleeding rates than sorafenib (25.2 versus 17.3 percent), including gastrointestinal bleeding (7 versus 4.5 percent) and variceal bleeding due to portal hypertension (2.4 versus 0.6 percent) [51]. Therefore, the risk of bleeding should be adequately assessed when targeting anti-angiogenic agents are used in neoadjuvant regimens, and endoscopy or therapy prior to neoadjuvant therapy should be necessary, or targeted agents should be avoided.
Before starting neoadjuvant immunotherapy, patients should be routinely screened for the functional reserve of various organs, including blood routine, liver function, renal function, thyroid function, cardiac enzymes, brain natriuretic peptide, urine routine, electrocardiogram, chest CT, etc., as well as inflammatory markers (such as C-reactive protein, interleukin), etc. At present, several guidelines have been issued for irAEs in China, proposing their own grading standards and management strategies [49,52]. For grade 1 irAEs, treatment is usually not required, and ICIs can be continued in most cases, but patients should be closely monitored for response. Grade 2 irAEs require ICI to be withheld until adverse effects are resolved, and if the adverse effects do not resolve after discontinuation, steroid therapy may be used depending on the severity of organ damage. Grade 3~4 irAEs require immediate start of steroid therapy. Specialist assistance is recommended for all grade 2 and above irAEs, as well as symptomatic endocrine irAEs such as diabetes mellitus and thyroid disease. For immune-related hepatitis that may occur after immunotherapy, pathological focus should be on lobular inflammation and hepatocyte punctate necrosis, manifold edema, small cholangitis and neutrophil infiltration, venous endotheliitis and paravenous tissue cell aggregation, and fibrin annular granuloma formation. Referral to a specialist should be recommended for vital organ-specific inflammatory response syndromes (pancreatitis, hypophysitis, pneumonia, myocarditis, neurological disorders, rheumatic diseases, and systemic autoimmune diseases), regardless of the severity of the irAE.
Recommendation 11: The most common irAEs in neoadjuvant immunotherapy for liver cancer are skin toxicity, endocrine system toxicity, pneumonia and gastrointestinal toxicity, etc., and the baseline function of each organ needs to be routinely screened before treatment, including blood routine, liver and kidney function, thyroid function, cardiac enzymes, electrocardiogram, chest CT and other examinations, grade 1 irAE usually does not need treatment, grade 2 irAE needs to be suspended until the adverse reaction is relieved, grade 3~4 irAE needs to be treated with steroids (evidence level 1, recommended strength A).
7. Adjuvant therapy after surgery for liver cancer
When the neoadjuvant regimen showed good results, it indicated that the patient was sensitive to the neoadjuvant regimen, and it was a reasonable choice to continue to use the original regimen as adjuvant therapy after surgery. If the sensitive neoadjuvant therapy is target-immune systemic therapy, the target-immune therapy should be continued after surgery, and if the sensitive neoadjuvant therapy is local therapy such as interventional or radiotherapy, the postoperative adjuvant therapy should refer to the recommendations on interventional and radiotherapy in the Chinese Expert Consensus on Postoperative Adjuvant Therapy for Liver Cancer (2023 Edition) [53]. The choice of postoperative treatment should be carefully considered based on the principles of both efficacy and safety [53]. If the adjuvant treatment regimen is a combination of multiple drugs, such as targeted combined immunization, dual immunization combination, etc., the original regimen or some of the drugs in the original regimen should be selected according to the patient's physical condition, adverse reactions and treatment tolerance.
Recommendation 12: For patients who respond to neoadjuvant therapy, postoperative adjuvant therapy is recommended to follow the original neoadjuvant regimen, and the specific regimen selection should follow the principle of equal emphasis on efficacy and safety (level of evidence 2, strength of recommendation B).
8. Timing of termination of neoadjuvant therapy and follow-up treatment after treatment failure
The treatment of disease progression in the process of neoadjuvant therapy for liver cancer is one of the current problems faced by neoadjuvant therapy. During neoadjuvant therapy, alpha-fetoprotein, abnormal prothrombin and other indicators should be measured regularly, and imaging tests should be performed regularly to determine whether the tumor size has changed. Tumor progression detected during neoadjuvant therapy should first be evaluated for resectability. If the tumor remains resectable, it is recommended to discontinue the current neoadjuvant regimen and undergo surgery to remove the tumor as soon as possible. If the tumor has metastasized to distant sites or other conditions that are not amenable to surgery, it is recommended that the appropriate treatment regimen be strictly selected according to the relevant diagnosis and treatment guidelines based on the stage of the tumor [10,21].
In the event of treatment-related adverse effects during neoadjuvant therapy, the severity of the adverse effects should be assessed first. Except for grade 1 irAEs, grade 2~4 irAEs need to be discontinued. If the adverse reactions disappear after symptomatic treatment, the original drug can be continued or reduced as appropriate according to the patient's physical condition and treatment tolerance. If the patient remains intolerant, discontinuation of the current neoadjuvant regimen may be considered.
Neoadjuvant therapy failure is due to tumor progression and worsening of underlying liver disease. When the cause of failure is that the tumor has not been remissioned, it is necessary to develop an individualized follow-up treatment strategy for the patient according to the previous treatment method and the characteristics of disease progression. If the underlying liver disease progresses, especially if serious adverse effects associated with systemic therapy occur, aggressive symptomatic supportive and palliative care should be considered.
Recommendation 13: For patients who have failed neoadjuvant therapy, an individualized follow-up strategy should be chosen, depending on the previous treatment modality and disease progression (level of evidence 3, strength of recommendation B).
9. Conclusion
In recent years, local therapy for liver cancer (HAIC therapy, radiotherapy, etc.) has achieved certain results in the field of neoadjuvant therapy, especially the great progress of neoadjuvant immunotherapy, which is likely to become the main development direction in the future due to its efficacy, safety and unique advantages. Ongoing high-quality clinical trials are expected to provide more solid evidence-based evidence for neoadjuvant therapy for liver cancer. Based on the latest clinical trials and evidence-based medical evidence, the Chinese Expert Consensus Collaboration Group on Neoadjuvant Therapy for Liver Cancer will continue to update this consensus to provide more in-depth theoretical and clinical guidance for the preoperative treatment of liver cancer, aiming to further reduce the recurrence rate of liver cancer after surgery and improve the long-term survival rate of liver cancer patients.
Member of the editorial board of the Chinese Expert Consensus on Neoadjuvant Therapy for Liver Cancer (2023 Edition).
Chairman: Wang Xuehao (The First Affiliated Hospital of Nanjing Medical University)
Vice Chairman (in alphabetical order of surname): Chen Minshan (Sun Yat-sen University Cancer Center), Cai Xiujun (Sir Run Run Shaw Hospital, Zhejiang University School of Medicine), He Xiaoshun (The First Affiliated Hospital of Sun Yat-sen University), Li Qiang (Tianjin Medical University Cancer Hospital), Li Xiangcheng (The First Affiliated Hospital of Nanjing Medical University), Liang Tingbo (The First Affiliated Hospital of Zhejiang University School of Medicine), Liu Jun (The Provincial Hospital Affiliated to Shandong First Medical University), Liu Lianxin (The First Affiliated Hospital of University of Science and Technology of China), Liu Xiufeng (Eastern Theater General Hospital), Liu Rong (The First Medical Center of the PLA General Hospital), Lv Yi (The First Affiliated Hospital of Xi'an Jiaotong University), Pu Liyong (The First Affiliated Hospital of Nanjing Medical University), Qin Lunxiu (Huashan Hospital Affiliated to Fudan University), Shen Feng (The Third Affiliated Hospital of Naval Medical University), Sun Beicheng (The First Affiliated Hospital of Anhui Medical University), Sun Huichuan (Zhongshan Hospital Affiliated to Fudan University), Yang Yang (The Third Affiliated Hospital of Sun Yat-sen University), Xia Qiang (Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine), Yong Zeng (West China Hospital, Sichuan University), Bixiang Zhang (Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology), Jiye Zhu (Peking University People's Hospital)
Secretary-General: Xia Yongxiang (The First Affiliated Hospital of Nanjing Medical University)
Members (in alphabetical order of surname): Bai Xueli (The First Affiliated Hospital of Zhejiang University School of Medicine), Bai Dousheng (Subei People's Hospital Affiliated to Yangzhou University), Bie Ping (The Third Affiliated Hospital of Chongqing Medical University), Cheng Feng (The First Affiliated Hospital of Nanjing Medical University), Cong Wenming (The Third Affiliated Hospital of Naval Medical University), Fan Xiangjun (The Affiliated Hospital of Nantong University), Guo Rongping (Sun Yat-sen University Cancer Prevention and Treatment Center), Guo Wenzhi (The First Affiliated Hospital of Zhengzhou University), Jin Bin (Qilu Hospital of Shandong University), Li Bin (The First Affiliated Hospital of Xiamen University), Li Wei (China-Japan Friendship Hospital of Jilin University), Liu Jianhua (The Second Hospital of Hebei Medical University), Lu Qian (Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University), Lv Ling (The Affiliated Hospital of Xuzhou Medical University), Ni Yong (The First Affiliated Hospital of Shenzhen University), Peng Tao (The First Affiliated Hospital of Guangxi Medical University), Qin Lei (The First Affiliated Hospital of Soochow University), Qin Xihu (The Second People's Hospital of Changzhou City), Song Jinhua (The First Affiliated Hospital of Nanjing Medical University), Tianqiang Song (Cancer Hospital of Tianjin Medical University), Kaishan Tao (Xijing Hospital of Air Force Medical University), Liming Wang (The Second Affiliated Hospital of Dalian Medical University), Lu Wang (Cancer Hospital of Fudan University), Weihu Wang (Cancer Hospital of Peking University), Weilin Wang (The Second Affiliated Hospital of Zhejiang University School of Medicine), Sanrong Xu (Jiangbin Hospital Affiliated to Jiangsu University), Xiao Xu (The First People's Hospital of Hangzhou Affiliated to Zhejiang University School of Medicine), Yan Yang (The First Affiliated Hospital of Nanjing Medical University), Yang Zhengqiang (Cancer Hospital, Chinese Academy of Medical Sciences), Zha Wenwen (Yancheng First People's Hospital), Zhang Chuanyong (The First Affiliated Hospital of Nanjing Medical University), Zhang Zhihong (The First Affiliated Hospital of Nanjing Medical University), Zhu Haidong (Zhongda Hospital, Southeast University), Zhu Zhijun (Beijing Friendship Hospital, Capital Medical University)
Authors: Zhang Yaojun (Sun Yat-sen University Cancer Center), Wang Feng (Eastern Theater General Hospital), Zhang Hui (The First Affiliated Hospital of Nanjing Medical University), Chen Zhiqiang (The First Affiliated Hospital of Nanjing Medical University)
Secretarial Group: Zhang Bin (Affiliated Hospital of Xuzhou Medical University), Tang Weiwei (The First Affiliated Hospital of Nanjing Medical University), Cao Hengsong (The First Affiliated Hospital of Nanjing Medical University)
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