Current status and progress of interventional treatment for primary hepatocellular carcinoma

Primary hepatocellular carcinoma (HCC) is a common malignant tumor in the gastrointestinal system, with high incidence, high recurrence rate, poor prognosis and very low 5-year survival rate. At present, the use of interventional-based non-surgical comprehensive treatment of HCC has made great progress, and its efficacy has been clinically recognized, now the status and progress of interventional treatment of HCC is reviewed. 1.1 Transcatheter hepatic artery chemoembolization (TACE) is the main method for the treatment of intermediate and advanced HCC. The principle is to make the tumor ischemic and necrotic by embolizing the tumor blood supply artery, which can help the second stage resection. In addition, the efficacy of TACE for small hepatocellular carcinoma is also certain and comparable to surgical resection. The main indications are: surgical resection is not curative and liver function is still good, no portal trunk cancer embolism; tumor volume does not exceed 70% of the whole liver; those who intend to have second-stage resection; post-surgical prophylaxis, etc., without serious liver and kidney dysfunction. The shortcomings of TACE are that the tumor is prone to recurrence and metastasis, which often requires multiple treatments. Even complete embolization cannot guarantee complete tumor inactivation, and the residual tumor cells can gradually adapt to the hypoxic microenvironment under the regulation of specific mechanisms, with high expression of vascular endothelial growth factor and increased invasive metastatic ability. In recent years, the application of ultramicrocatheter technology has achieved liver segment or subhepatic segment embolization, which further improves the efficacy. The survival rates of patients treated with TACE were 92.5% and 88.9%, respectively, and even those with portal vein cancer embolism treated with TACE could prolong the mean survival time to 9.5 mo, with a 1-year survival rate of 25%. 1.2 Thermo-chemoembolization is based on the difference of heat sensitivity of cells, normal cells start to die when heated above 45℃, while tumor cells generally only tolerate 40℃-43℃. The factors affecting its efficacy are mainly the time, temperature, total amount and flow rate of perfusion solution, and the continuity of heat therapy, etc. Experiments have proved that the scientific temperature of perfusion solution is (47.55±0.44)℃, and the perfusion is maintained for 10min to The short-term efficiency and 1-year survival rate reached 79.2% and 50.0%, respectively. Indications: primary and metastatic single tumor with diameter <3 cm or number of lesions <3: those with diameter 3-8 cm and number of lesions less than 3, those with large amount of ascites, severe jaundice and liver failure, and those with severe coagulation dysfunction are contraindicated, and other scholars have conducted studies on portal vein embolism (PVE) and combined hepatic artery-portal embolization. Studies have confirmed that PVE has been widely used before hepatectomy with positive efficacy; however, due to the extensive lesions of some HCC, even after PVE, the residual liver still cannot fully compensate for the functional needs, and TACE is the preferred method of treatment at this time. 2.Non-vascular interventional therapy mainly refers to percutaneous percutaneous local ablation therapy, i.e. ablation needle through percutaneous hepatic percutaneous route to the tumor target area, using chemical and/or physical methods to destroy the tumor bed, mainly including the following. 2.1 Chemical ablation 2.1.1 Percutaneous intratumoral anhydrous ethanol injection: It is a chemical ablation, and the treatment mechanism is the protein coagulation effect of anhydrous ethanol and secondary microvascular embolization, because the resistance in the tumor foci is lower than the surrounding liver tissues, anhydrous ethanol can diffuse well in the tumor foci and play a therapeutic role, which has the advantages of low cost, safety and few complications. For patients with tumor diameter <3cm and tumor number ≤3, the 5-year survival rate can reach 64.7% after percutaneous ethanolinjection (PEI), but the disadvantage is that it is often difficult to achieve complete inactivation for larger tumors and multiple injections are required. The new ablation needle has been introduced to improve the efficacy of PEI, which consists of 18G injection needle bar and 3 retractable sub-needles with 4 injection holes on each sub-needle, and after puncture into the tumor, the umbrella-shaped sub-needle is unfolded from the apex of the mother needle, and ethanol is injected from 12 injection holes at the same time to extend the diffusion range to a diameter of 5.5 mm. Ethanol is injected from 12 injection holes simultaneously to extend the diffusion range to a tumor of 5 cm in diameter, but repeated treatment is still required. Whether anhydrous ethanol or acetic acid is injected, it can cause immediate tissue necrosis, thus forming a protein necrosis film around the injection needle, which restricts drug dispersion and makes it difficult to distribute the drug evenly in the tumor. A single-center trial in France showed that fluoroscopic CT-guided percutaneous injection of acetic acid for the treatment of small hepatocellular carcinoma has good recent efficacy and low risk, and can be used for those with ascites and severe coagulation dysfunction, but the high recurrence rate of HCC and the multi-point origin of the lesion limit the clinical application of this technique. At present, acetic acid ablation has been eliminated in China, and it is only used in a few countries in Japan. PEI and TACE have their own characteristics: TACE is difficult to inactivate tumor at once, and the recurrence rate and metastasis rate are high. The combination of TACE and PEI can complement each other and significantly improve the survival rate compared with single treatment. 2.2.1 Percutaneous radiofrequency ablation therapy: Percutaneous radiofrequency ablation therapy is a new technology of minimally invasive tumor thermal therapy, and the efficacy of percutaneous radiofrequency ablation therapy (RFA) in treating HCC has been clinically confirmed. Research shows that RFA can inhibit tumor angiogenesis, reduce tumor blood supply and restrict tumor growth, so it is one of the treatment mechanisms of RFA to stop tumor progression at the stage of tumor angiogenesis. The main progress of RFA in recent years is that the clinical application of multi-fork electrode needle, cluster electrode needle and electrode needle with cooling device has reduced the tissue carbonization and improved the efficacy. The complete ablation rate reached 92.5%, and the cumulative survival rates at 1, 2, 3, 4 and 5 years after surgery were 95.1%, 85.6%, 75.7%, 60.7% and 47.5%, respectively. In view of the similar indications of RFA and PEI, Seror et al. compared the efficacy of the two, and their 2-year overall survival rates were 91.2% and 70.8%, respectively, with significant differences, suggesting that the efficacy of RFA is better than PEI, which is consistent with Doros' report that the overall efficacy of RFA is better than PEI for small hepatocellular carcinoma with single, ≤5 cm in diameter or the number of tumors 1-3 and ≤3 cm in diameter, small hepatocellular carcinoma, Small hepatocellular carcinoma, inoperable or postoperative recurrent hepatocellular carcinoma and hepatic metastatic carcinoma are all indications for RFA treatment, and the efficacy of RFA for small hepatocellular carcinoma is equivalent to that of surgery, and the 3-year survival rate is significantly higher than that of 3-5 cm tumors (61.46% vs. 38.71%); when the tumor diameter is >5 cm, the 3-year survival rate is only 27.62%. Shibata et al. also found no difference in the efficacy of TACE combined with RFA for small hepatocellular carcinoma compared with single RFA in a controlled study. For HCC lesions adjacent to the gastrointestinal tract or located at the top of the diaphragm and surrounded by huge blood vessels, RFA technique is more risky, and PEI can be a candidate treatment method at this time; its efficacy is more satisfactory when combined with TACE or RFA for HCC. Although it has been reported that RFA can cause 0.5%-2.8% incidence of needle tract implantation, needle tract ablation can basically avoid this complication, which should be regarded as contraindicated for patients with severe liver dysfunction, massive ascites, coagulation dysfunction, diffuse hepatocellular carcinoma, pregnancy and pacemaker installation. As a new technique for the treatment of HCC, RFA lacks large samples, prospective controlled studies and long-term follow-up studies, and how to improve the efficacy of RFA has been a major clinical problem. It is now recognized that the combination of multiple minimally invasive therapies, sequential combined application and combined biological therapy is a comprehensive treatment. 2.2.2 Percutaneous microwave ablation therapy: Percutaneous microwave ablation therapy (PMCT) significantly improves the volume of one-time tumor inactivation through the combination of multiple needles, etc. The role of non-surgical treatment in HCC is becoming increasingly prominent, and its principle is similar to that of RFA, which increases the temperature of tumor tissue Shibata et al. compared the efficacy of PMCT and RFA on HCC and concluded that there was no significant difference in the complete ablation rate and tumor residual rate, but the number of treatments in the RF group was significantly less than that in the microwave group, while the treatment time was significantly longer than that in the microwave group. The ablation rate, adverse effects, complications and survival rate of the two methods were also compared by Lv Mingde et al. The indications are similar to RFA, but the difference is that PMCT can be applied to HCC patients with pacemakers, and because microwave ablation is more commonly used in Japan and China, the results of the study are different because of the different equipment used by each other. 2005 American College of Hepatology included RFA and PEI in the treatment guidelines for liver cancer. 2.2.3 High-intensity focused ultrasound: The clinical application of high-intensity focused ultrasound (highintensityfocusedultrasound, HIFU) began with the treatment of hypertrophy of the prostate, and at the end of 1997, China took the lead in using this independent intellectual property technology in the clinical treatment of tumors, and made China’s research level in this field in the international leading position. The mechanism of action is to use the physical characteristics of ultrasound such as visualization, tissue penetration and focusing, through its heating effect, cavitation effect and mechanical effect, to directly destroy deep tumor tissues in vivo by locating them from outside the body, causing a sudden increase in local tumor tissue temperature (up to 65℃ or more) and rapid coagulation of intracellular proteins, resulting in irreversible death of tumor cells. Although HIFU can treat deep tumors, the treatment is time-consuming, and for masses with irregular margins, the treatment may produce “off-target” phenomenon due to the effect of respiratory motion, which affects the efficacy. Compared with other thermal ablation therapies, the range of tissue coagulation is smaller, and the ablation time is too long for larger tumors, which has been gradually eliminated due to the popularity of other thermal ablation methods. 2.3 Cold ablation is mainly argonhelium knife cryo-ablation (argonheliumsystemcryo-ablation, AHSCA): In 1850, Arnott reported the application of frozen salt solution (about -18℃~-24℃) as cold medium for the local treatment of progressive breast cancer and cervical cancer, and found that the tumor shrank and the pain was reduced, which created the pioneer of cryotherapy for tumors. The first one. Its principle is to produce tumor necrosis effect through two mechanisms of cell damage and vascular damage, cell damage is mainly produced by the harmful effect of freezing and thawing cycle instantly, and the progressive microcirculatory failure causes vascular damage and blood flow stagnation, resulting in tissue necrosis; it has the advantages of precise positioning, accurate temperature control and timely monitoring, which opens up a new field of HCC treatment. In addition, AHSCA can stimulate the body’s anti-tumor immune function: the After surgery, the tumor macromolecular antigen component is obviously reduced, small molecule protein antigen and macrophages are increased, INF and PGE, activity is enhanced, Ma Zhigang et al. showed that 81.2% of the masses shrink or form cavities after treatment, 66.7% of AFP turn negative, 6mo survival rate after surgery reaches 76.9%, the ice ball coverage in cold ablation requires more than 1cm of tumor edge shown by imaging This is the key to prevent recurrence and improve the efficacy. Cryoablation is certainly effective in reducing the tumor load in the short term, and the survival rate is comparable to that of surgery, but long-term clinical follow-up studies are urgently needed to fully evaluate the efficacy. The factors affecting the efficacy of AHSCA include target tissue injury temperature and freezing-retreatment rate, number of ablations, tissue physical parameters and cold knife radius, etc. Different tissue physical parameters (such as blood perfusion rate, metabolic rate, etc.) result in different ice ball diameters, and the higher the blood perfusion rate and metabolic rate, the smaller the size of the ice ball formed under the same conditions, and the smaller the effective treatment radius, so the implementation of AHSCA should Therefore, the differences in freezing and rewarming characteristics between different tissues, the size and location of the tumor should be fully considered when performing AHSCA, so that the treatment plan can be individualized to ensure the efficacy. Regarding the complications and safety evaluation of various ablation procedures, there is a general consensus that the complication and lethality rates are low, and multicenter studies show that the lethality rate of physical ablation is about 0.1%-0.5%, and the incidence of serious and minor complications are 2.2%-3.1% and 5%-8.9%, respectively. In short, ablation therapy for HCC is relatively safe. With the continuous progress of basic medical research, the interventional treatment of HCC has gradually advanced from clinical research to basic research, and a new generation of molecular targeting drugs has been applied in the clinic and combined with interventional radiology to achieve better efficacy and broad application prospects. According to the target and nature of drugs, molecular targeted drugs are mainly classified into the following categories: small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, anti-EGFR monoclonal antibodies, anti-HER-2 monoclonal antibodies, Bcr-Abl tyrosine kinase inhibitors, vascular endothelial Growth factor receptor inhibitors, anti-CD20 monoclonal antibodies, IGFR-1 kinase inhibitors, ubiquitin-1 proteasome inhibitors, etc. Although there are more types of targeted therapies, the drugs currently used for the treatment of HCC are still representative of sorafenib and ricardine (131I-labeled methotrexate). 3.1 Interventional targeted therapy 131I methotrexamab (Licartin) is a new 131I-labeled monoclonal antibody used for guided radiation therapy of HCC. The target antigen of the antibody, Hab18G/CD147, is an HCC-specific antigen that plays an important role in tumor invasion and metastasis, and the specific binding of the monoclonal antibody to the target antigen can reduce the signaling of metastatic and recurrence channels of cancer cells, which can not only bring The specific combination of monoclonal antibody and target antigen can reduce the signaling of cancer cell metastasis and recurrence channels, which not only can bring radioactive 131I to tumor cells to realize the direct irradiation effect on tumor cells, but also itself can kill tumor cells through antibody-dependent cytotoxic effect, while blocking its effector cells from secreting matrixmetalloproteinase (MMP) to prevent further spread of cancer cells, achieving a dual therapeutic effect. lycopene treatment Clinical trials and preliminary clinical applications of HCC have shown that it is efficacious, safe and feasible, and has a certain tumor shrinkage rate for all types of hepatocellular carcinoma with blood supply. In recent years, as a new treatment strategy transarterial injection of radioactive microspheres and particulate technology is emerging. 3.2 Systemic targeted therapy Sorafenib is the first to market and the only multi-target, multi-kinase inhibitor approved by the FDA for the treatment of HCC, and the first treatment proven to extend survival by inhibiting tumor recurrence and metastasis, extending median survival (10.7movs6.5mo) and time to disease progression (5.5movs2.8mo), compared with placebo. The tolerability was good, and the phase I and II trials of sorafenib plus adriamycin also confirmed the effectiveness of the combination therapy, with a tendency to prolong the time to disease progression compared with adriamycin. The key issue to focus on and address in the future is how to combine sorafenib with conventional surgery, TACE and other molecularly targeted therapeutic agents to maximize the efficacy, and studies have shown that sorafenib combined with interventions (TACE , RFA, etc.) for advanced hepatocellular carcinoma, the tumor response rate increases, prolonging the time of disease progression, and patients benefit clinically significantly, in order to inhibit different growth and invasion pathways of hepatocellular carcinoma, other molecularly targeted drugs are in the stage of development and clinical trials, which have a good clinical prospect. 3.3 Gene therapy refers to the treatment of disease by expressing genes that are not originally expressed in specific target cells, or by shutting down or inhibiting abnormally expressed genes in a specific way, which is the hot spot of tumor treatment, and the main methods are: suicide gene therapy, introduction of oncogenes (such as p53) or antisense genes (such as ras, mys, etc.) therapy, immune factor gene therapy (such as IL-2, GM-CSF, IFN, etc.), etc, GM-CSF, IFN, etc.) and RNA interference technology. At present, there are more clinical reports of super-selective transhepatic arterial introduction of P53 for HCC, and the initial efficacy is positive. In addition, some Chinese medicine can help improve the clinical efficacy of HCC, especially with minimally invasive intervention, radiotherapy, chemotherapy, etc., which can improve patients’ clinical symptoms, reduce adverse reactions and prolong survival, which is worthy of reference. Conclusion At present, there are more mature interventional techniques for the treatment of HCC, each with its own advantages, and TACE combined with other interventional treatment methods to perform sequential and comprehensive treatment is recognized to improve the efficacy, but many specific technical routes in clinical practice are not standardized, and more randomized controlled studies are needed to achieve standardized and individualized unification of treatment protocols to obtain a better prognosis, and we can be convinced that: with the continuous improvement of basic research on HCC and the continuous improvement of interventional techniques, we can improve the clinical efficacy of HCC. We can be convinced that with the deepening of the basic research of HCC and the continuous progress of the interventional treatment technology, the combination of interventional radiology and molecular biology has a good development prospect and will make the treatment of HCC enter a new era.