Interventional treatment for small hepatocellular carcinoma Ablation therapy, which can also be called destructive therapy, is a local treatment method with potential curative value for small hepatocellular carcinoma, mainly including chemical ablation (percutaneous anhydrous alcohol injection, percutaneous acetic acid injection), high-temperature ablation (radiofrequency ablation, microwave thermocoagulation, laser ablation, high-temperature saline or high-temperature distilled water, etc.) and low-temperature ablation (cryotherapy such as argon helium knife). The efficacy is related to the size of the liver cancer, the number of tumor foci, the Child-Pugh score, and the basal alpha-fetoprotein (AFP) level. Studies have shown [2] that the complete necrosis rate of tumors treated by ablation can reach more than 80% when the tumor diameter is <3 cm; when the tumor diameter is 3-5 cm, the complete necrosis rate of tumors treated by ablation is reduced to about 50%. Chemical ablation Percutaneous ethanol injection (PEI) is the first minimally invasive technique used for ablation of liver cancer. The postoperative tumor necrosis rate after PEI is directly related to the tumor size, and the postoperative complete necrosis rate can reach more than 95% for tumors ≤2 cm in diameter; when the tumor diameter increases to 3 cm, the postoperative complete necrosis rate decreases to 70% [2]. 70% [2]. In addition, the rate of complete tumor necrosis after PEI is related to the degree of tumor differentiation and radiological characteristics (with or without pseudo-envelope) [3]. The main factors affecting survival after PEI are liver function, tumor size/number, and AFP. in some clinical studies with good case selection, the 5-year survival rate of PEI for early-stage hepatocellular carcinoma can reach 40%-50% [2, 4, 5, 6]. the best outcome of PEI for hepatocellular carcinoma is for small hepatocellular carcinoma with Child grade A, single nodule, and tumor foci <3 cm. Due to the poor diffusion capacity of alcohol, the use of acetic acid, a chemical ablative with greater permeability than anhydrous alcohol, was attempted in the 1990s for the treatment of hepatocellular carcinoma. A randomized controlled study showed that percutaneous acetic acid injection (PAI) was more effective than anhydrous alcohol injection, with 2-year survival rates of 92% and 63%, respectively, and intrahepatic recurrence rates of 8% and 37%, respectively [7]. Hyperthermic ablation Radiofrequency ablation (RFA) is a new technique for liver cancer treatment developed in the last decade. Despite its short application time, it has gained a place in clinical practice, especially in the treatment of small hepatocellular carcinoma [8]. Currently, the internationally recognized indications suitable for RFA treatment are (1) single nodal hepatocellular carcinoma with lesions less than 5 cm, preferably less than 3 cm; (2) less than three intrahepatic lesions, each not exceeding 3 cm; (3) metastatic hepatocellular carcinoma with resected primary foci, metastases less than 5 cm in diameter and less than three in number; (4) patients without surgical indications, or those who refuse surgery and those who need delayed surgery; (5) The main drawbacks of RFA are: (1) heat sinks, where the heat generated by RF is carried away by the blood flowing in the nearby large blood vessels, which reduces the therapeutic effect. (2) Damage to the adjacent organs of the tumor. (3) For larger tumors, the rate of tumor necrosis due to radiofrequency is low. The clinical application of microwave ablation is slightly later than that of radiofrequency ablation, and the principles of treating tumors are similar between the two. Non-randomized studies have shown the efficacy of microwave ablation, which can cause complete necrosis of some tumors [9]. Laser ablation has less clinical application, and limited data suggest that laser ablation is a promising treatment method. Cryoablation The principle of cryoablation technique is that the target tissue is subjected to a sudden drop in ultra-low temperature (-40°C to -100°C) environment, and ice crystals are rapidly formed inside and outside the cells, microvenules and microarteries, causing cell dehydration, rupture, and ischemic necrosis of tissue due to small vessel thrombosis.Wang et al [10] used percutaneous puncture argon helium knife cryotherapy for hepatocellular carcinoma ≤3 cm and >3 cm in diameter. The tumor necrosis rates on imaging were 100% and 90%, respectively. However, in general, there is little literature on cryoablation for hepatocellular carcinoma, and too little information is available for evaluation. Comparison of ablative treatment methods At present, there are a wide variety of local ablative treatment methods applied in clinical practice, but the most commonly used treatment methods with more accumulated experience are PEI, RFA and microwave ablation. RF and microwave ablation can achieve more than 90% complete tumor necrosis rate for tumors ≤5 cm in diameter, compared to PEI for tumors ≥3 cm in diameter, which has a significantly lower rate of complete tumor necrosis. Non-randomized studies have shown that the efficacy of radiofrequency and microwave ablation for small hepatocellular carcinomas, including survival and local tumor control rates, is superior to anhydrous alcohol injection. Four recently published randomized controlled studies, three of which confirmed this conclusion [11-13], and another showed no difference in 2-year survival but a significant decrease in local recurrence rate [4] (see Table 1 for details). As for the superiority of radiofrequency or microwave, there is no definite conclusion. Although Shibata et al [14] compared two approaches, radiofrequency and microwave, for the treatment of small hepatocellular carcinoma, this trial had limited value for evaluation due to the lack of observation of patient survival. In this trial, microwave treatment of liver cancer had lower rates of complete tumor necrosis than RF and higher rates of local tumor recurrence than RF, but neither was significantly different. Therefore, a large randomized controlled study to screen the therapeutic value of both is necessary. There is less information on cryoablation and laser ablation for the treatment of liver cancer, and there are no randomized controlled studies with other ablation methods. In summary, radiofrequency ablation and microwave ablation are preferred for ablative treatment of early-stage hepatocellular carcinoma. If the tumor diameter is <3 cm and the patient is not suitable for radiofrequency or microwave therapy, anhydrous alcohol injection is also a better choice. Acetic acid, high-temperature saline or high-temperature distilled water can be used instead of anhydrous alcohol for the treatment of liver cancer. Table 1 Randomized controlled study of different ablation methods for small hepatocellular carcinoma Authors (year) Method Case Tumor size Complete necrosis rate (%) Survival rate (%) Local recurrence rate (%) 1 year 2 years 3 years 4 years Lin et al (2005) RFA 62 ≤3 cm 96 93 81 74* ND 14* PEI 62 88 88 66 51* ND 34* PAI 63 92 90 67 53* ND 31* Shiina et al (2005) RFA 118 ≤3cm 100 97 91 ND 74* 2 PEI 114 100 92 81 ND 57* 11 Lin et al (2004) RFA 52 ≤4cm 96 90 82* ND ND ND 18* PEI 52 88 85 61* ND ND 45* High dose PEI 53 92 88 63* ND ND ND 33* Lencioni et al (2003) RFA 52 ≤5cm 91.6 100 98# ND ND ND 4* PEI 50 82.6 96 88# ND ND ND 38* Shibata et al (2002) RFA 36 90% ≤3cm 96 ND ND ND ND ND 12# Microwave 36 89 ND ND ND ND ND 24# Note: RFA radiofrequency ablation; PEI percutaneous ethanol injection, PAI percutaneous acetic acid injection, ND not described, * P < 0.05, # P > 0.05 Ablative therapy versus surgical resection Surgical resection is the main treatment for early-stage hepatocellular carcinoma, and patients who undergo surgical resection can obtain more satisfactory immediate and long-term treatment results. In some studies with mainly single nodal lesions and good liver function reserve, the 5-year postoperative survival rate of patients could reach 60%-70% [15-16], and from the perspective of intention-to-treatment, surgical resection is the preferred method for treating early-stage hepatocellular carcinoma. However, surgical resection is not 100% curative treatment, such as in China, Zhou Xinda et al [16] used surgery to resect 1,000 cases of small hepatocellular carcinoma, however, the curative rate was only 80.5%. Moreover, the recurrence rate of small hepatocellular carcinoma was as high as 70% at 5 years after surgery [17]. As previously mentioned, ablation for small hepatocellular carcinoma can achieve complete tumor necrosis rates of more than 90%, and in some clinical studies with better outcomes, patients also had a 5-year survival rate of 70% after surgery [4]. Therefore, it is difficult to make a fair evaluation of the advantages and disadvantages of both from the analysis of non-randomized or observational studies only. Recently, 2 small randomized controlled studies compared the efficacy of ablation and surgical treatment, and the results of Huang et al [18] showed that for small hepatocellular carcinoma ≤3 cm in diameter, PEI had the same efficacy as surgery, with no significant difference in the 1-5-year survival rate and local recurrence rate; the results of Minhua Chen et al [19] showed that the 1-3-year survival rate after radiofrequency treatment was the same as surgical resection, and the local tumor There was also no difference in the control rate, and for stage Ia small hepatocellular carcinoma with tumor diameter ≤3 cm, the recent efficacy of radiofrequency treatment was slightly better than that of surgical resection. The above study shows that ablation therapy is expected to be one of the preferred methods for the treatment of small hepatocellular carcinoma less than 3 cm in diameter. However, the value of ablation versus surgery in the treatment of small hepatocellular carcinoma needs to be evaluated in a large randomized controlled study. Table 2 Randomized controlled studies of ablation versus surgery for small hepatocellular carcinoma Authors (year) Method Case Tumor size Survival rate (%) Local recurrence rate (%) 1 year 2 years 3 years 4 years 5 years Huang et al (2005) PEI 36 ≤3cm 100 100 97 92* 46* 47* resection 36 97 91 88 88* 82* 39* Chen Minhua et al (2005) RFA 65 ≤5cm 93 82 65* – – 23* resection 47 93 86 67* – – 25* Note: RFA radiofrequency ablation; PEI percutaneous ethanol injection, * P > 0.05 chemoembolization chemoembolization (transcatheter arterial chemoembolization (TACE) is a technique of embolization with iodine oil chemoemulsion or granular embolization agent via arterial puncture and superselection into the tumor-supplying artery. For small hepatocellular carcinoma with a diameter of <5 cm, endoscopic hepatic segmental resection can be achieved by using a microcatheter technique, superselective cannulation to the hepatic segmental or subsegmental arteries, pressurized injection of larger amounts of iodine oil chemoemulsion to completely fill the small terminal tumor arteries and veins, and embolization with gelatin sponge particles or PVA particles to embolize the tumor donor arteries.Matsui et al [20] used segmental chemoembolization Nishimine et al [21] reported the results of segmental chemoembolization in 36 cases of small hepatocellular carcinoma <3 cm in diameter, and the survival rates at 1, 2, 3, and 4 years after surgery were 100%, 85%, 73%, and 73%, respectively. The results of the domestic study were similar [22]. These results suggest that the efficacy of TACE for small hepatocellular carcinoma is comparable to that of surgery. However, due to the lack of randomized controlled studies, the value of TACE versus surgery for small hepatocellular carcinoma cannot be fairly evaluated yet. Interventional treatment of intermediate and advanced hepatocellular carcinoma TACE TACE is is the main treatment for intermediate and advanced hepatocellular carcinoma. However, it is controversial whether TACE procedure can improve the survival of patients with hepatocellular carcinoma in the early stage. Several recent Meta-analyses on the efficacy of embolization therapy for hepatocellular carcinoma showed that TACE was not only effective in controlling local tumor growth, but also significantly increased the 2-year survival rate of patients [23-24]. A recent Meta-analysis included seven randomized controlled studies (see Table 3 for details), and the results showed that TACE procedure is an effective method for treating patients with intermediate to advanced hepatocellular carcinoma. However, if the indication is not properly selected, the anticancer benefit of TACE may be offset by the damage to liver function caused by chemotherapeutic agents and embolization. Alvarez R [25] et al. concluded that the benefits of TACE are much greater in patients with Child-Pugh A and B liver function than in those with Child-Pugh C. Llovet et al [23] also concluded that multinodular patients without vascular infiltration and with Child-Pugh C liver function are more likely to benefit from TACE. Llovet et al [23] also considered patients with multiple nodules without vascular infiltration and with Child-Pugh class A liver function as the most suitable population for TACE. Domestically, the suitability of TACE is mainly determined by the patient's liver function status (e.g. ascites, hepatic encephalopathy, albumin and bilirubin levels). In conclusion, there are no accepted criteria for the treatment of TACE. Large randomized controlled studies based on Child-Pugh classification, or Okuda staging, or TNM staging may help to address this issue. In embolization therapy, although chemotherapeutic agents are used in most patients, there is no evidence which of the currently used chemotherapeutic agents is more effective, and even in combination they do not improve patient survival as a result. Several studies have shown that embolization with low-dose chemotherapeutic agents has the same efficacy as embolization with conventional doses of chemotherapeutic agents [26]. In three randomized controlled studies [27], there was no significant difference in survival between patients with hepatocellular carcinoma who underwent embolization alone (transcatheter arterial embolization, TAE) or TACE. This suggests that most patients did not benefit from chemotherapeutic agents and therefore there is an urgent need to develop chemotherapeutic agents that are effective in chemoembolization of hepatocellular carcinoma. The addition of gelatin sponge pellets/PVA embolization of the tumor donor artery after TACE helps to improve the survival of patients with hepatocellular carcinoma, and the addition of PVA embolization may be more effective. The interval between TACE procedures is determined by the tumor response and the patient's condition, usually 4-12 weeks apart. Table 3 Randomized controlled study of TAE/TACE versus conservative treatment of moderately advanced hepatocellular carcinoma Authors (year) Treatment modality Number of treatments Number of cases Child Grade A (%) Survival rate (%) 1 year 2 years Lin et al. (1988) TAE 2.1 21 ND 42 25 IV 5-Fu 21 13 13 Pelletier et al. (1990) TACE 2 21 88 24 - conservative 21 33 - Group d'Etude et de Traitment du Carcinome He´patocellulaire (1995) TACE 2.9 50 100 62 38 conservative 49 43 26 Bruix et al. (1998) (1998) TAE 1.4 40 82 70 49 Conservative 40 72 50 Pelletier et al. (1998) TACE 2.8 37 76 51 24 Conservative 36 55 26 Lo et al. (2002) TACE 4.8 40 ND 57 31* Conservative 39 32 11* Llovet et al. (2002) TAE 3.1 37 70 75 50* TACE 2.8 40 82 63* Conservative 35 53 27* Note: TAE, transcatheter arterial embolization, TACE transcatheter arterial chemoembolization, ND not described, * P <0.05 TACE combined with ablative therapy Although TACE significantly improves the survival of intermediate to advanced hepatocellular carcinoma, according to the theory of incomplete clearance characteristics of angioembolization proposed by the author [28], it is often difficult to completely necrotize larger tumors after TACE, and postoperative residual cancer tissue, recurrence, and intrahepatic metastasis limit the further improvement of TACE efficacy. residual and recurrent foci after TACE The volume is relatively small, which is theoretically suitable for local ablation therapy. In addition to the above-mentioned local ablation treatment methods, the author has developed a simple and effective iodine oil chemoemulsion intratumoral injection, which is mainly used for chemical ablation of residual and recurrent foci after TACE that cannot be embolized via arteries. The method can be briefly described as follows: chemotherapeutic drugs are dissolved and mixed with super-liquidated iodine oil to form an emulsion, which is injected into the tumor with a fine needle puncture under fluoroscopic surveillance until the tumor is completely filled. Several other non-randomized studies have shown that the administration of PEI after TACE improves the survival of patients with hepatocellular carcinoma. However, most of the randomized controlled studies [29-31] showed that TACE combined with PEI improved the tumor-free survival of patients with hepatocellular carcinoma but did not prolong the survival of patients. This suggests that factors affecting the survival of patients with hepatocellular carcinoma, in addition to tumor recurrence, some underlying conditions of patients, such as liver function, may play a more important role. Large-scale randomized controlled studies based on Child-Pugh classification and liver cancer staging may help to determine the role of TACE combined with PEI in the treatment of intermediate to advanced liver cancer.The value of TACE combined with radiofrequency in the treatment of liver cancer has also been explored, with most non-randomized studies showing comparable efficacy of TACE combined with radiofrequency ablation to TACE alone.2 retrospective studies, on the other hand, showed [32- 33], combined radiofrequency ablation after TACE is a feasible and safe method that can effectively improve the survival of patients. However, the results of randomized controlled studies are not available and the value of the combination of the two treatments cannot be judged yet. Conclusion The results of several randomized controlled and meta-analysis studies indicate that multiple interventional treatments for small hepatocellular carcinoma have achieved similar efficacy to surgical resection and are superior to surgical treatment in terms of safety, recurrence rate, reproducibility, complication rate and indications. TACE is the first choice for palliative treatment of hepatocellular carcinoma because it can effectively control the local growth of tumor and improve the survival of patients, but the candidate criteria, chemotherapeutic agents and intervals of TACE for hepatocellular carcinoma treatment need to be further investigated, and the role of TACE in combination with other local treatments needs to be further observed.