Primary liver cancer (abbreviated as hepatocellular carcinoma) is one of the most common malignant tumors, characterized by high malignancy, infiltration and metastasis, and poor prognosis. Globally, there are more than 600,000 new cases of hepatocellular carcinoma each year, with the fifth highest incidence rate and the third highest number of tumor-related deaths. China has more than 300,000 new cases each year, accounting for more than half of the global incidence, and its mortality rate ranks second only to lung cancer, and even jumps to the first place in some rural areas with high incidence. In recent years, with the establishment of high-risk groups and the popularization and development of screening methods such as AFP and imaging technology, the detection rate of small hepatocellular carcinoma (≤5cm in diameter) has increased significantly.
In the past, the so-called comprehensive treatment of liver cancer was mainly reflected in the non-surgical or post-surgical resection treatment of unresectable liver cancer or mid- to late-stage liver cancer, but now the concept of comprehensive treatment is expanded and penetrated into the whole process of liver cancer treatment. Take small hepatocellular carcinoma as an example, its treatment means has evolved from single surgical resection in the past to a new pattern of “triple-legged surgical resection, liver transplantation and local ablation therapy, and multidisciplinary comprehensive treatment”. However, in terms of clinical reality and evidence-based medical research results, surgical resection is still the preferred treatment for hepatocellular carcinoma, but due to many factors such as tumor status, liver disease background, especially liver reserve function, the surgical resection rate is only about 20%, and the postoperative recurrence rate is high. Therefore, experts try to make a more scientific and accurate clinical staging of liver cancer, and then choose different treatment strategies according to the staging, and combine multiple treatment methods organically and sequentially, that is, comprehensive treatment, in order to improve the overall efficacy of liver cancer.
1. Overview of liver cancer staging and treatment methods
The clinical staging of tumor is the basis for selecting appropriate treatment methods and comparing the efficacy of different treatment methods, as well as the basis for determining the prognosis of patients. The Chinese University of Hong Kong prognostic coefficient (CUPI) scoring system, the Japanese TNM staging method (LCSGJ) and JIS score method, as well as the Chinese staging. The UICC and AJCC TNM staging has been considered the best staging method for solid tumors, and the AJCC/UICC has added the liver fibrosis score in recent years and recommended its combined application with TNM score to assess However, since the prognostic impact of liver function is not considered, this staging method is not highly accepted internationally. The Chinese Anti-Cancer Association Hepatocellular Carcinoma Staging Committee 2001 (CS) has borrowed the TNM staging and emphasized the status of liver function in the staging.
The BCLC staging method, on the other hand, takes into account the tumor, liver function and systemic conditions of the patient more comprehensively, and is linked to the principles of treatment, highlighting its guiding role in the selection of therapeutic measures and supported by high-level evidence-based medicine, and is currently the most recognized and commonly used staging method in the international arena. In addition, the presence or absence of portal hypertension as a staging criterion is difficult to operate in practice and is not quite suitable for our specific national conditions and clinical reality, and can only be used as an important reference. In conclusion, various staging methods have their own advantages and disadvantages. Okuda staging, BCLC staging and CLIP staging may be more suitable for patients with non-surgical hepatocellular carcinoma, while TNM staging and CS staging may be more suitable for patients with surgical treatment. At present, there is a need for a clinically accepted staging method that is consistent with Chinese conditions, has good predictive ability, and can provide important guidance for treatment evaluation. The integrated BCLC and TNM staging is the ideal choice at present.
The treatment methods for hepatocellular carcinoma are many and varied, but they can be initially divided into radical treatment and palliative treatment according to the expected local therapeutic effect of the tumor. Radical treatment mainly includes surgical resection and liver transplantation, and in recent years, there is a trend to include radiofrequency and microwave local ablation treatment for small hepatocellular carcinoma as radical treatment. Palliative treatments are most representative of hepatic artery embolization chemotherapy (TACE), including radiotherapy, chemotherapy, targeted therapy and other local and systemic treatments. It can also be directly divided into surgical resection, liver transplantation, local ablation, TACE, and systemic therapy according to the different treatment methods. Since there are many treatment methods for liver cancer, many clinical departments such as hepatobiliary surgery, transplantation surgery, interventional medicine, medical oncology, radiotherapy, traditional Chinese medicine, infection and so on are involved in clinical practice. At present, although they all recognize the importance of comprehensive treatment, most of them are still working individually and fighting alone. Choosing scientific and reasonable comprehensive treatment methods according to tumor stage and staging in order to prolong patients’ life is the most urgent and realistic issue in liver cancer treatment.
2. Selection of comprehensive treatment plan for different stages of liver cancer
In 2011, the Medical Secretary of the Ministry of Health of China organized liver cancer experts in different fields nationwide to formulate the “Standard for the Treatment of Primary Liver Cancer” and proposed a multidisciplinary comprehensive treatment model for liver cancer. These criteria, which are also listed in order of general condition (PS), liver function (ChildCPugh classification), extrahepatic metastasis, vascular invasion, and tumor size, are the main basis for treatment selection. In order to facilitate understanding, the author classifies hepatocellular carcinoma into early stage (and very early stage), intermediate stage, progressive stage and end stage with reference to BCLC staging model, and interprets the comprehensive treatment of hepatocellular carcinoma with relevant literature for reference.
2.1 Early stage and very early stage liver cancer
According to BCLC staging PS 0-2, Child-PughA or B, isolated tumor regardless of size, no vascular invasion, no lymph node metastasis, and no distant metastasis are considered early stage hepatocellular carcinoma. BCLC staging and the European and American Association for the Study of Liver Diseases (EASL-AASLD) further refer single hepatocellular carcinoma with diameter <2 cm as very early stage hepatocellular carcinoma. Early and very early stage hepatocellular carcinoma is classified as T1N0M0 or stage I in TNM staging. There are also Milan's criteria to define single tumor ≤5cm in diameter, or multiple tumors ≤3, and maximum diameter ≤3cm as early stage liver cancer. Surgical resection, local ablation and liver transplantation are the main themes of treatment for early and very early stage hepatocellular carcinoma, among which surgical resection is the preferred treatment, and the effect of anatomical hepatectomy is better than non-anatomical hepatectomy. For some isolated giant tumors, if the volume of the residual liver is estimated to be insufficient after resection, the tumor can be shrunk by preoperative transhepatic artery chemoembolization (TACE) before resection or combined with portal vein embolization of the liver lobe where the tumor is located, so that the proposed liver can compensate for the hyperplasia before resection.
If the liver reserve function is poor and it is estimated that it cannot tolerate surgical resection, local ablation can also be performed for tumor lesions that have shrunk after TACE. For some patients with small hepatocellular carcinoma in deep liver or central right lobe of liver with high surgical risk or poor hepatic reserve function, local ablation therapy can be directly selected. Local ablation mainly includes radiofrequency, microwave, freezing, high power ultrasound focused ablation and anhydrous ethanol injection treatment. Currently, the most applied ablation methods are radiofrequency and microwave thermal ablation therapy. The literature reports that the therapeutic effect of local thermal ablation therapy (RFA and MWA) for small hepatocellular carcinoma ≤3 cm is similar to that of surgery and can achieve the effect of radical ablation. Because of the advantages of minimally invasive and simple, local ablation is increasingly used in clinical practice, especially in the treatment of very early hepatocellular carcinoma, its 5-year survival rate can reach 78%, which has the tendency to replace surgical resection. Depending on the location of tumor, local ablation can be performed through three routes: ultrasound-guided percutaneous puncture, trans-laparoscopic and open surgery.
After local ablation treatment, imaging (e.g. enhanced CT, enhanced MRI, ultrasonography) should be strictly evaluated and followed up closely to prevent incomplete ablation or recurrence of satellite foci, and if necessary, supplemental ablation or other treatments should be combined, such as combined anhydrous ethanol injection for vascular or peribiliary treatment. Liver transplantation for early-stage hepatocellular carcinoma, although some studies have shown that its overall effect is better than hepatic resection, is generally only suitable for patients with poor liver reserve function due to severe organ shortage and high cost. As for hepatic artery embolization chemotherapy ( TACE), it is not used as the main treatment for small hepatocellular carcinoma, but for patients with multiple tumors, or those whose pathological examination reveals that they have high risk factors for recurrence, postoperative TACE can timely detect and control microscopic lesions that cannot be detected intraoperatively, and it is meaningful to improve the therapeutic effect of surgical resection and local ablation and reduce the recurrence rate after surgery.
2.2 Mid-stage liver cancer
Combining BCLC and TNM staging, those with PS 0-2 score, liver function ChildCPugh A or B, isolated tumor, with vascular invasion or multiple tumors ≤5cm in diameter, no lymph node metastasis and no distant metastasis are classified as intermediate stage hepatocellular carcinoma (TNM stage II, T2N0M0). A single liver tumor with intrahepatic vascular invasion refers to the invasion of non-major branch vessels, which can generally be surgically removed together with the invaded vessels to achieve the curative effect. The proportion of patients with mid-stage hepatocellular carcinoma accounts for about 20-30% of all hepatocellular carcinoma cases in clinical practice, and the choice of treatment is whether TACE or surgery is preferred. From the literature, the results of surgery or TACE alone are not satisfactory, and the 3-year survival rate does not exceed 30%. EASL-AASL guidelines for hepatocellular carcinoma recommend TACE as the first choice, while in China and Japan and other Asian countries, surgical resection is the first choice, and TACE is the first choice for inoperable cases.
Vascular invasion and multiple tumors are all high-risk factors for recent recurrence after surgery, so a meticulous individualized treatment plan must be designed for the specific condition. During surgery, not only should the specific operation style and the scope of liver resection be formulated according to the liver function, the size and distribution of tumor and the invasion of the vasculature, but also timely hepatic arteriography should be performed after surgical resection to understand whether there is tumor residue in the residual liver, and TACE should be performed if necessary to control the lesion and prevent recurrence. In the author’s opinion, because the disease is more complicated in this stage, the choice of treatment methods is much debated, and there is a chance to obtain radical (resection or liver transplantation) treatment through comprehensive treatment to lower the tumor stage, so there is more space to improve the treatment effect, which is the focus of multidisciplinary collaborative integrated medical model (MDT) and an important focus of research on comprehensive treatment of hepatocellular carcinoma. Taking TACE and surgical resection treatment as the main axis, the appropriate combination and sequential application of local ablation therapy (multiple lesions, ≤3 cm in diameter) and selective liver transplantation (meeting UCSF criteria) are important directions to further improve the efficacy. Whether the application of systemic chemotherapy and targeted drugs can further prolong survival remains to be studied and observed more.
2.3 Progressive hepatocellular carcinoma
Hepatocellular carcinoma with obvious clinical symptoms, PS 0-2 score, liver function Child-PughA or B, multiple tumors >5cm in diameter, invasion of portal vein or main or major branches of hepatic vein, lymphatic or extrahepatic organ metastasis, i.e. TNM stage III and IV are considered as progressive hepatocellular carcinoma. TACE, systemic chemotherapy, targeted therapy and radiation therapy are the main means of treatment for progressive liver cancer. However, if the patient’s general condition and liver function are good and the tumor can be resected, palliative resection of the tumor can also be considered. Intraoperative ablation is feasible for subfoci deep in the residual liver or at the edges of the liver. When hepatocellular carcinoma directly invades the surrounding organs, if the primary liver tumor can be resected, it should be removed together with the invaded organs; for isolated or limited metastases in a lung lobe of distant organs such as the lung, they can also be removed in due course. After surgery, TACE, local ablation, systemic therapy (including targeted therapy), radiotherapy, etc. should be combined according to the condition. Studies have shown that the 3-year survival rate of some progressive hepatocellular carcinoma can be more than 30% with positive palliative surgery combined with TACE and local ablation, and individual cases can even survive for more than 5 years.
2.4 End-stage hepatocellular carcinoma
Patients with P-S3-4 score or Child-Pugh grade C liver function are all end-stage liver cancer patients. At this time, patients can only partially take care of themselves or not, and their life expectancy is not more than 3 months. Most of them cannot bear strong anti-tumor treatment, and the main treatment methods are symptomatic treatment and supportive treatment. Only for some patients with end-stage liver disease resulting in liver function loss, if they meet the criteria for liver cancer liver transplantation (UCSF criteria), they can choose liver transplantation, which is theoretically the most ideal treatment means as it can remove the background of liver disease and cure the tumor by transplanting a new liver.
3.The status of systemic therapies in the comprehensive treatment of liver cancer
Liver cancer is a systemic disease occurring in the liver, so theoretically, systemic or systemic treatment is an integral part of the comprehensive treatment of liver cancer as well as local treatment such as liver resection, local ablation and TACE. The “holistic” principle of liver cancer treatment includes systemic treatment, which mainly includes antiviral therapy, molecular targeted therapy and systemic chemotherapy, bioimmunotherapy, Chinese herbal medicine and symptomatic support therapy, etc.
3.1 Anti-viral therapy for HBV/HCV-related hepatocellular carcinoma
HBV and HCV infection plays an important role in the development of hepatocellular carcinoma. Therefore, antiviral therapy for patients with HBV/HCV-associated hepatocellular carcinoma has reached a consensus and established its important position in the comprehensive treatment of hepatocellular carcinoma, and antiviral therapy should be early, efficient and long-term. Antiviral therapy can improve liver function and create favorable conditions for other treatments against HCC. In addition, antiviral therapy can suppress viral replication of HBV/HCV to the lowest level, reduce or delay the recurrence of HCC and improve the quality of life. Even patients who are HBV DNA and HCV RNA negative and receive oncology treatment should pay high attention to the reactivation of the virus and closely monitor the viral replication. There are currently two classes of anti-HBV drugs, namely nucleoside (acid) analogs (NAs) and interferon alpha (IFNα). Clinically, the nucleoside (acid) analog entecavir is the drug of choice for antiviral treatment of hepatitis B-related liver cancer due to its potent anti-HBV ability, low resistance rate and good safety profile. The standard treatment regimen for chronic HCV infection is pegylated interferon alpha (PEG-IFNα) in combination with ribavirin (RBV) therapy.
3.2 Molecular targeted therapy and systemic chemotherapy
In recent years, molecularly targeted drugs, represented by Sorafenib, have made breakthroughs in the systemic treatment of hepatocellular carcinoma and have become the standard of care for advanced or progressive hepatocellular carcinoma. Some studies have shown that TACE combined with Sorafenib for the treatment of intermediate to advanced hepatocellular carcinoma can improve the efficacy and prolong the survival. It remains to be seen whether the combination of sorafenib can prevent recurrence and metastasis after surgery in patients with hepatocellular carcinoma treated with radical resection, liver transplantation, or local ablation. It is worth mentioning that the side effects of sorafenib are also large and need to be taken seriously.
The overall effect of systemic chemotherapy for hepatocellular carcinoma is not satisfactory, and there is no chemotherapy regimen recognized as effective. Although some studies have found that FOLFOX4 regimen and arsenious acid injection can benefit the survival of some patients with intermediate to advanced hepatocellular carcinoma, the actual clinical value is limited due to the high toxicity and side effects of chemotherapy drugs themselves, which have adverse effects on liver and kidney functions.
3.3 Bioimmunotherapy and Chinese medicine treatment
Biological immunotherapy of liver cancer is a hot spot of research in recent years. And with the rapid development of modern molecular biology technology and genetic engineering technology, it has opened up a whole new field for biological immunotherapy of liver cancer and has developed into a new mode of liver cancer treatment. The experimental research of various biological immunotherapy including immunotherapy, gene therapy and stem cell therapy has achieved promising results and shown good application prospects.
Chinese medicine treatment, on the other hand, is a characteristic content of liver cancer treatment in China, which has certain value in relieving symptoms of middle and late stage liver cancer and alleviating complications or side effects caused by surgery, TACE, radiotherapy and chemotherapy, and can be applied as one of the means of comprehensive treatment for adjuvant treatment of liver cancer at different stages. There are many clinical cases in which the disease has been stabilized and long-term survival has been achieved through the application of traditional Chinese medicine.
3.4. Symptomatic and supportive treatment
Patients with hepatocellular carcinoma are mostly combined with chronic liver disease, so they need to pay attention to the protection of liver function during treatment, minimize the damage to liver and avoid excessive use of hepatotoxic drugs. In addition, liver cancer is a highly malignant tumor, and the overall treatment effect is still unsatisfactory, which is a great psychological blow to patients and their families. According to different symptoms, timely treatment such as analgesia, yellowing reduction, diuresis, anemia correction, nutritional support, albumin supplementation and ascites puncture should be provided to improve patients’ survival quality and prolong their survival period as much as possible.
In conclusion, with the deepening of basic and clinical research on liver cancer in recent years, the treatment concept of liver cancer has also changed greatly, especially in view of the complexity of liver cancer and the limitations of various treatment methods, it has become the consensus of liver cancer treatment to develop individualized and comprehensive treatment plan according to the patient’s characteristics, and the selection process of specific treatment methods is actually a scientific and dialectical clinical The selection process of specific treatment methods is actually a scientific and dialectical clinical decision-making process. However, it is indisputable that in the predictable future, the treatment policy of “early diagnosis and early treatment” of liver cancer will not change, and the comprehensive treatment based on “surgical resection, local ablation and liver transplantation” will remain the main mode of treatment for early-stage liver cancer. The development of minimally invasive surgery will add to this model, and the research on imaging and tumor markers reflecting the biological behavior of liver cancer is expected to provide a more valuable basis for the accurate definition of early-stage liver cancer. In contrast, the treatment paradigm of mid- to late-stage liver cancer may undergo historical changes with the establishment and effective operation of MDT teams, and with the in-depth research and elucidation of the priorities, sequences and specific values of various treatments in the comprehensive treatment system, especially the development and application of new systemic therapeutic drugs. It should be emphasized that the individualized comprehensive treatment of liver cancer needs to follow the requirements of standardization and standardization, and the personal arbitrariness of physicians in choosing treatment methods should be avoided in order to effectively improve the efficacy of liver cancer. However, the real improvement or breakthrough of the treatment effect of liver cancer may depend on further research on the basic research of liver cancer, especially on the mechanism of cancer transformation and the mechanism of recurrence and metastasis.