Primary liver cancer (abbreviated as liver cancer) is one of the 10 most common and serious malignant tumors in the world, with 260,000 cases per year (4% of malignant tumors), 42.5% of which occur in China, and the incidence has been on the rise in recent years. At present, liver cancer is the first among the deaths of malignant tumors in rural areas of China, and the second after lung cancer in urban areas. Therefore, it is of great importance to improve the diagnosis and treatment of liver cancer. Therefore, it is very important to improve the diagnosis and treatment of hepatocellular carcinoma. The author reviews and outlooks the interventional treatment methods of hepatocellular carcinoma based on the related literature and a lot of clinical data.
Zhang Zhigao, Department of Gastroenterology, General Hospital of Jinan Military Region
1 The status of interventional therapy in the treatment of hepatocellular carcinoma
Although surgical resection is the first choice in the treatment of liver cancer, the key to achieve satisfactory curative effect lies in early diagnosis. Historically, it is difficult to detect liver cancer at early stage, and once detected, it is mostly in middle or late stage. According to statistics, the surgical resection rate is 5%-25%, and the survival rate is only 30% at one year after surgery, and the quality of survival is poor. Interventional therapy mainly based on hepatic artery chemoembolization (TACE) has achieved definite efficacy and is considered as the preferred method among non-surgical treatments for hepatocellular carcinoma, and has become an effective measure before second-stage surgery. In addition, with the emergence of microcatheter super-selective cannulation technology, local interventional treatment of tumor can be performed without basically damaging normal liver tissues, which is of great clinical significance for patients with combined cirrhosis and poor liver function reserve.
2 Methods of interventional treatment for hepatocellular carcinoma
In the past 20 years, interventional scholars at home and abroad have done a lot of work and achieved promising results in the interventional treatment of liver cancer, and explored many effective interventional treatment methods. They are broadly divided into two categories: percutaneous transvascular treatment techniques and percutaneous non-vascular treatment techniques.
2.1 Percutaneous transvascular treatment techniques
2.1.1 Transcatheter arterial embolization (TAE) TAE was developed on the basis of super-selective hepatic arteriography, and the clinical application of this method was first reported by Goldstein in 1976. In China, Lin Gui first reported the clinical application of using TAE for HCC in 1983. Later, with the development and application of various embolic agents, TAE has been used more and more widely in clinical practice for palliative treatment of inoperable or postoperative recurrent hepatocellular carcinoma cases, and has even become an optional method alongside with surgical resection. In recent years, based on the technology of TAE, many new embolization methods have been carried out and promoted clinically with good therapeutic effects, such as: combined hepatic artery-portal vein embolization (TAPVE), hepatic subsegmental embolization (THSAE), etc.
2.1.2 Combined hepatic artery-portal vein embolization (TAPVE) TAE is performed simultaneously with percutaneous portal vein puncture to embolize the portal branches of the segment where the tumor is located, and this technique is often monitored by real-time television fluoroscopy. The rate of necrosis was higher in the TAE group.
2.1.3 Hepatic segmental and subsegmental embolization (THSAE), also known as cement therapy, is a super-selective cannulation of LP-TAE, and Nakamura suggested that iodine oil in excess of a certain limit could return from the hepatic sinusoids to the small branches of the portal vein for the purpose of portal embolization. Coaxial catheterization, drug-assisted methods (e.g., vasoconstrictors), or direct superselective catheter insertion are often used. It is indicated in cases where the tumor is located in a single or a few hepatic segments or subsegments, with or without subfoci, or in patients who are not suitable for conventional hepatic artery embolization due to severe abnormal liver function.
2.1.4 Temporary blockade of the hepatic vein followed by hepatic artery chemoembolization (TAE-THVO) For confined hepatic lobar and segmental tumors and those with arteriovenous fistulae. Kim Saw-right et al. found an increase in the number of arteries in the picture by blocking the inferior hepatic vein arteriography. This method can avoid embolic agent into the body circulation and make TAE treatment feasible for patients with arteriovenous fistula, while increasing the concentration of local chemotherapeutic agents and acting as TAPVE.
2.1.5 Sandwich therapy: Embolization of the distal segment of the hepatic artery with iodine-containing oil, infusion of chemotherapeutic agents, and then embolization of the proximal segment of the artery. Clinical studies have shown that this method can lead to complete necrosis of small tumors and a significant decrease in AFP.
2.1.6 Multiple arterial perfusion embolization Hepatocellular carcinoma often has parasitic arteries or vagus arteries. Embolization of these side branches along with embolization of hepatic arteries can greatly improve the efficacy.
2.1.7 Permanent hepatic artery embolization Studies have shown that the internal diameter of the artery embolized by different embolic agents varies. The arteries embolized by gelatin sponge particles are in the middle artery of 1200-1500 μm; while microspheres and alcohol can enter the micro-artery of about 100 μm in diameter and are not absorbed [12], and some scholars call embolization performed by such embolic agents permanent hepatic artery embolization.
2.1.8 Hepatic arterial infusion (transcatheter arterial infusion, TAI) TAI technique was applied in the clinic before TAE. However, TAI alone is not effective in the treatment of hepatocellular carcinoma, and it is rarely used alone in clinical application now. Some scholars use balloon to block the blood flow for intra-arterial drug infusion, which can increase the drug concentration in the tumor area (30 times), and the drug stays for a long time, and the effect is better than general infusion. Yang Jijin et al. achieved better efficacy by heating and reperfusion of chemotherapeutic drugs for the treatment of hepatocellular carcinoma in rats. Some other scholars have used arterial boosting method to perfuse chemotherapeutic drugs by taking advantage of the poor response of tumor arteries to vasoactive substances.
2.1.9 Implantable port system The implantation of catheter and perfusion pump can be done surgically through the abdomen or through the femoral or subclavian artery, and Pentecost suggested that the establishment of a catheter system could result in higher local drug concentrations in the liver. Shan Hong [16] et al. applied this method to treat metastatic hepatocellular carcinoma and found that those with liver metastases originating from gastrointestinal cancer had a better outcome with a median survival of 17.6 months and 1 and 2 year survival rates of 68.4% and 39.5%, respectively.
2.1.10 Intra-arterial embolization combined with internal radiation therapy This method can not only embolize and block the tumor blood supply more thoroughly, but also implement radiation killing effect in tumor tissues with high concentration and uniform distribution of internal radiation source, which has low local radiation reaction. The 90Y glass microspheres and 32P glass microspheres made in China have been used in clinical practice and have achieved satisfactory efficacy. In addition, in order to block the parasitic blood vessels of hepatocellular carcinoma, Iwamoto [19] used silicone rubber film implanted on the surface of liver, and then performed TAE and portal perfusion therapy, and the survival of patients was prolonged, and some people called this method as isolation therapy.
2.2 Percutaneous non-vascular treatment techniques
2.2.1 Chemotherapy
2.2.1.1 Percutaneous ethanol injection therapy (PEI) In 1983, Sugiura et al. successfully treated experimental liver cancer foci in mice by injecting anhydrous ethanol, and this method was gradually promoted after Livraghi reported the clinical application of anhydrous ethanol for small liver cancer in 1983. Clinical studies of such cases were also reported by Liu Limin et al. in China. In addition, some scholars have shown that anhydrous ethanol injection at 60℃～70℃ can induce tumor necrosis, which is called HOT PEI. the ideal indication for PEI is tumor diameter ≤3cm and no more than 3 nodules. Its main disadvantages are that it requires multiple punctures, multiple sessions and multiple amounts of anhydrous ethanol, and it cannot kill tumors that cannot be detected by current imaging, and it is not ideal for blood-rich and giant hepatocellular carcinoma.
2.2.1.2 Percutaneous acetic acid injection therapy (PAI) The puncture technique, treatment method and mechanism of action are similar to those of PEI, but the dose and number of treatments used are significantly reduced. The quantitative analysis of tumor necrosis was 90%-100% and 64%-90%, suggesting that 50% acetic acid can replace anhydrous ethanol to achieve better efficacy.
2.2.1.3 Direct injection chemotherapy (DICT) Some scholars advocate the addition of ultrasound-guided DICT after TAI/TAE, which is considered to have a higher survival rate than monotherapy, but no large group of cases have been reported.
2.2.2 Physical therapy
2.2.2.1 Percutaneous hot water or saline injection therapy (PHOT or PSIT) In 1993, Ohishi used hot water and in 1994, Honda used hot saline to treat hepatocellular carcinoma with satisfactory results of tumor necrosis and no significant toxic side effects. It can be safely used for the treatment of liver cancer with larger diameter.
2.2.2.2 Percutaneous laser-induced thermo therapy (LITT) In 1985, Hashimoto first reported US-guided percutaneous LITT for hepatocellular carcinoma, and other scholars have subsequently done related clinical studies, which concluded that the tumor necrosis rate of this method could reach 74.3% without serious complications.
2.2.2.3 Percutaneous microwave hyperthermia therapy (PMHT) US-guided percutaneous microwave hyperthermia therapy is performed by placing a microwave electrode needle connected to a microwave tissue coagulator in the tumor, and then choosing the appropriate power and emission time for microwave treatment according to the size of the tumor. In recent years, this method has been used to treat patients with liver cancer who have failed TAE/TAI, and Dong Baowei et al. believe that this is a safe and effective method for the non-surgical treatment of liver cancer.
2.2.2.4 Percutaneous radio-frequency ablation (RFA) In recent years, the literature has reported that RFA is mainly used for the treatment of small hepatocellular carcinoma and metastatic tumors. Therefore, it can be used in combination with TAI or TAE. Recently, some scholars have proposed some modified measures, such as RFA + temporary portal vein obstruction, bipolar radiofrequency electrocautery, etc., in order to improve the efficacy and promote tumor tissue necrosis.
2.2.2.5 Percutaneous cryoablation (PCA) was firstly reported by D′Agostino in 1995. Although this method has efficacy, it is not better than other methods and has many troublesome aspects, so it is not widely used in clinical practice.
2.2.2.6 Electrochemical therapy (electro chemo therapy,ECHT) Fewer reports have been published on the electrochemical treatment of hepatocellular carcinoma by percutaneous hepatic puncture under CT or MR guidance, which is based on the theory of biological closed circuit and has the characteristics of wide range and ability to kill cancerous tissues at one time, but it is not effective for multiple, diffuse lesions and masses near the hilar structure.
2.2.3 Percutaneous intratumoral injection of radionuclide Many scholars have adopted CT or US guided intratumoral injection of 131Ⅰ, which have certain effect, but no breakthrough has been seen.
3 Biological therapy
3.1 Gene therapy is divided into percutaneous puncture and transcatheter tumor gene therapy. The former is to directly introduce the target gene into the liver cancer under the guidance of US, CT or MR, which has the advantages of reliable guidance and easy and intuitive operation. In 1997, Gelczer et al. reported that ultrasound-guided percutaneous intratumoral injection of Allovection (containing HLA-B7 gene) for the treatment of liver metastases elicited an immune response, but no significant tumor shrinkage was observed. The latter involves precise and specific delivery of the DNA vector complex to the target tissue vasculature through a catheter; embolization techniques are then used to prolong the contact time between the vector and the target cells and increase the uptake of the vector complex by the target tissue. Hao Qiang et al. showed that recombinant adenovirus injected via hepatic artery route has organ-targeted expression in vivo.
3.2 Immuno therapy Patients with hepatocellular carcinoma often have declining immune function as their disease progresses, and it has been found that various immunostimulatory cytokines such as interleukin, tumor necrosis factor and interferon injected into the tumor can enhance the anti-tumor immunity of patients.
3.3 Biologically guided therapy Guided therapy is to treat liver cancer by specific antibodies carrying anti-cancer drugs, biotin and radioactive elements to attack the specific antigens of the tumor itself. By releasing the biomissile directly to the tumor localization via hepatic artery cannula, the three major problems in guided therapy, namely dilution, physiological barrier and non-specific absorption, can be reduced or avoided, thus maximizing its therapeutic effect.
3.4 Induction of differentiation therapy The morphology, function and metabolism of tumor cells are considered to be a dedifferentiation phenomenon. Transdermal or transcatheter injection of differentiation inducers makes tumor cells re-differentiate and change their malignant biological behavior, which has been experimentally and clinically proven.
3.5 Anti-tumor vascular therapy Tumor growth can be divided into avascular phase and vascular phase. avascular phase tumors grow slowly or remain dormant for a long time. folkman et al. found that neovascularization is necessary for the growth and maintenance of solid tumors and their metastases. Some scholars have found that many malignant tumors also form vascular inhibitory factors such as Angiostatin and Endostatin. In response to these theories, anti-vascular therapy has emerged in recent years to cut off the nutritional blood supply on which tumors grow and indirectly stop the development and metastasis of tumors. It can be divided into antineovasculatural therapy and anti-angiogenetic therapy. With the continuous development of biomedicine, vascular growth inhibitors such as platelet factor 4 (PF-4), nicotinol (TNP-470), endostatin and angiostatin combined with interventional therapy for intrahepatic arterial or intra-focal perfusion are expected to become important magic weapons to inhibit recurrence and metastasis of hepatocellular carcinoma.
3.6 Immunoembolization therapy Early literature reported the treatment of primary hepatocellular carcinoma with OK-432; recently, Ye Qiang et al. treated hepatocellular carcinoma with OK-432-like immunomodulator sapropterin and iodine oil emulsion, and concluded that immunoembolization therapy could significantly improve the cellular immune status of hepatocellular carcinoma patients.