As a common and frequent disease worldwide, hepatocellular carcinoma has been receiving attention from various clinical and basic related disciplines. However, as a solid tumor in a substantial organ, it lacks satisfactory means in diagnosis and treatment. Enhanced CT combined with AFP is a milestone in the diagnosis of hepatocellular carcinoma, but it cannot achieve 100% diagnosis yet. Traditional hepatectomy has made outstanding achievements in the treatment of hepatocellular carcinoma, but its clinical application is greatly limited by its excessive trauma, high requirements on patients’ general condition, negative exploration, size of tumor and its relationship with large blood vessels and biliary tract, and low resection rate of advanced hepatocellular carcinoma.
In recent years, with the application and improvement of various minimally invasive techniques, it has provided new ways for the diagnosis and treatment of liver cancer; it has provided a clear diagnosis for patients with suspicion; it has provided treatment opportunities for patients who are not suitable for open surgery; and it has even achieved curative effect in some small liver cancer patients, which has made remarkable achievements. Therefore, minimally invasive techniques have a wide application prospect in the treatment of liver cancer, but there are many problems that need to be further solved. This article reviews the progress of minimally invasive techniques in the diagnosis and treatment of hepatocellular carcinoma in recent years.
For patients who cannot undergo surgery, there are many non-surgical methods used to treat liver cancer; percutaneous ablative treatment is preferred, while chemical ablation is usually done by alcohol injection. Physical ablation, radiofrequency ablation, is a relatively new technique that involves the placement of a high-frequency radiofrequency needle into the liver cancer mass, usually under the guidance of imaging surveillance equipment. A body of data suggests that both techniques result in tumor necrosis and have low mortality and morbidity. However, recent studies comparing alcohol injection with RF ablation have shown that RF ablation is more advantageous in terms of technical success and tumor-free survival.
TACE combined with radiofrequency ablation (RFA) Radiofrequency ablation (RFA) is now widely used for the treatment of small nodules in hepatocellular carcinoma. The complete remission rate for tumors less than 3 cm in diameter is over 80%, while the remission rate for tumors 3-5 cm in diameter is only 50%. Randomized controlled studies have shown that RFA has similar survival rates to hepatectomy for small hepatocellular carcinoma. rFA is indicated for patients with larger tumors (3-5 cm), multiple tumors (3 nodes of 3 cm), and liver function loss (Child-pugh class B).
The recurrence rates of small hepatocellular carcinoma treated with RFA were 18-22% at 1 year, 30-48% at 2 years, and 83% at 5 years. Multifactorial analysis showed that recurrence was associated with low platelet levels (<1.0×1011L-1), degree of cirrhosis, cirrhosis, coagulation, prothrombin time >80%, multiple nodes, and histological Edmondson grading (grade II and III). Approximately 15% of patients with hepatocellular carcinoma are not suitable for RFA treatment due to the potential thermal damage to adjacent organs by RFA.
Based on these factors, although RFA has achieved better results in the treatment of hepatocellular carcinoma, it still cannot achieve the same remission rate and regression as surgical resection even when it is the first choice. Transarterial chemoembolization (TACE) is a palliative treatment for hepatocellular carcinoma and is mainly used for patients with stage B liver cancer in Barcelona. In recent years, it is also used to overtreat patients while waiting for a donor for liver transplantation. For unresectable hepatocellular carcinoma with large vascular supply, TACE can achieve partial remission rates of 15%-55% and can significantly alleviate tumor progression.
Hepatic artery radiotherapy embolization (TARE-Y90) TARE-Y90 is a relatively young interventional treatment method, which has little effect due to the dose limitation of extrahepatocellular radiation. tARE uses embolization agent as a carrier to exert internal radiation effect while embolization, which can effectively improve the efficacy. At present, I 131-iodine oil is mostly used in clinical practice. Its 1, 2 and 3-year survival rates have been reported to be up to 82%, 55% and 55%. With the continuous improvement of methods, TARE is a better choice for the treatment of liver cancer. Recent studies have shown that TARE-Y90 is better than TACE but in patients in the combined organ sharing network from T3 to T2.
Intrahepatic arterial I-131 methotrexate infusion, treated according to the principle of radioimmunity, is a new targeted drug with radionuclide labeled antibodies for the treatment of hepatocellular carcinoma (I-131 methotrexate). It is indicated for all hepatocellular carcinomas, especially those who are not suitable for TACE or who are ineffective or recurrent after TACE treatment. The control rate (CR+PR+MR+SD) for advanced primary hepatocellular carcinoma was over 80% in 108 uncontrolled open phase II clinical studies.
TACE combined with PVCE, transcatheter hepatic artery (TACE) and combined portal vein embolization (PVCE) refers to the insertion of catheters into the tumor-carrying hepatic artery and portal vein lobes (segments) branches for simultaneous embolization therapy. The low pressure and low velocity of portal vein prolongs the local residence time of drugs, which is conducive to killing cancer cells. TACE+PVEC is mainly suitable for primary hepatocellular carcinoma with arterial multiple chemoembolization causing occlusion of the corresponding hepatic artery, resulting in increased portal vein involvement in blood supply.
Preoperative TAPVE for hepatocellular carcinoma can shrink the lobe (segment) of the tumor-bearing area and hypertrophy the non-tumor-bearing area, which increases the liver reserve, thus reducing life-threatening complications after surgery, and can improve the safety of extensive resection of hepatocellular carcinoma. A foreign study reported that after hepatocellular carcinoma was treated with TACE combined with PVE, the necrosis rate of surgically resected specimens confirming the main tumor, intrahepatic metastases and portal vein aneurysm emboli was higher than that of the TACE group.
TACE combined with RFA or PEI treatment may allow a single electrode to produce a coagulative necrotic area greater than 5 cm in a single RF treatment due to the blockage of the hepatic artery blood supply using TACE which affects the heat convection of blood flow and reduces heat loss in the tissue, and the necrotic tissue and fibrosis within the tumor may alter the thermal conductivity of the tumor tissue, thus making it easier to conduct heat; for nodular hepatocellular carcinoma greater than 5 cm nodal hepatocellular carcinoma TACE combined with RF therapy is also very effective; meanwhile, TACE therapy can reduce the risk of needle tract seeding metastasis during RF therapy.
The nodules with a diameter of 3.5-8.5 cm can be more completely ablated after one or two RFA treatments after blocking the tumor arterial blood supply. 62 patients with unresectable hepatocellular carcinoma were treated with radiofrequency ablation after blocking the tumor arterial blood supply by balloon catheter or gelatin sponge by Rossl et al. The 1-year survival rate reached 87% without serious complications.
Yamasaki et al. obtained a larger volume of coagulative necrosis with balloon blockade of the hepatic artery followed by RFA for liver tumors than with RFA alone. Some scholars have achieved satisfactory results in radiofrequency ablation of liver tumors over 3.5 cm or adjacent to the hepatic vein or portal vein branches by using balloon to temporarily block the hepatic vein or segmental portal vein branches. yamakado et al. showed that the one-year survival of TACE combined with radiofrequency treatment was 98%, and the one-year survival was 100% for tumors less than 3 cm in diameter and 96.4 The one-year survival was 98% for those with tumors less than 3 cm in diameter and 96.4% for those larger than 3 cm. For larger non-nodular hepatocellular carcinoma, the combination of the two treatments still needs to be further investigated.
Since anhydrous ethanol destroys tumor cells, it also destroys and occludes tumor vessels, allowing further necrosis of tumor tissue that survives or continues to progress due to the presence of fine branches and collateral circulation or due to portal blood supply during TACE treatment, reducing the probability of recurrence. For larger hepatocellular carcinoma, tumor tissues are mostly parenchymal and there are often fibrous separations within the cancerous tissues, which hinder the diffusion of ethanol in the tumor, while the blood flow of large vascular-rich hepatocellular carcinoma dilutes ethanol and reduces its toxic effects, resulting in the poor effect of applying PEI alone for large hepatocellular carcinoma.
When TACE is combined with PEI, the tumor parenchyma is necrotic, and the ethanol is easy to diffuse, resulting in complete or most of the tumor foci are necrotic. Several domestic and foreign studies have shown that TACE combined with PEI for hepatocellular carcinoma is significantly better than TACE or PEI treatment alone in terms of survival evaluation. In general, the efficacy of TACE combined with RFA or PEI is better than that of single treatment.
The combination of TACE with microwave therapy, microwave therapy (MCT) is to use the thermal effect of microwave to coagulate, degenerate and necrotize tumor tissues to achieve the purpose of in situ inactivation or local eradication, MCT can also enhance the local and systemic cellular immune function of the body to further destroy tumor and residual cancer cells and prevent tumor recurrence, which may be an important reason for the good long-term efficacy and low recurrence rate of PMCT.
TACE combined with thermal microwave ablation for hepatocellular carcinoma is conducive to bringing their respective advantages into play and increasing the therapeutic effect: when heating the tumor, the blood circulation in and around the tumor can play a cooling effect, TACE can reduce the blood supply to the hepatocellular carcinoma tissue, reduce or eliminate this cooling effect and increase the necrotic volume of tumor thermal ablation; the thermal effect can increase the uptake of chemotherapeutic drugs by the tumor tissue, prolong the drug’s The thermal effect can increase the uptake of chemotherapeutic drugs by tumor tissue, prolong the residence time of drugs in tumor tissue, increase the sensitivity of tumor tissue to drugs, and improve the effect of chemotherapy; certain chemotherapeutic drugs such as mitomycin C, bleomycin, and cisplatin can prevent the occurrence of tumor heat resistance and enhance the anti-tumor effect of microwave. seki et al. reported that 18 patients with hepatocellular carcinoma with lesions <3 cm were treated with TACE combined with microwave therapy, and 17 cases were found to have complete tumor necrosis and no recurrence during the observation period.
TACE combined with argon helium knife treatment, argon helium knife is a new technology for tumor treatment emerged in recent years, which destroys tumor tissues through rapid freezing and thermal thawing. It can also promote the recovery of the body’s immune function and enhance the body’s ability to kill tumor tissues. Its shortcomings are that it is difficult to completely necrotize tumor cells at the edges of tumor nodes larger than 3 cm; for masses near the hilar region, puncture and freezing need to avoid damaging large arteries, veins and intrahepatic bold ducts; multi-point freezing can cause intrahepatic bleeding; larger-scale freezing treatment can aggravate liver function damage in patients with cirrhosis.
Clavien PA et al. concluded that the efficiency of TACE combined with Ar-He knife is better than that of TACE alone in the interventional treatment of hepatocellular carcinoma. TACE combined with laser therapy (LACE) can make up for the shortage of TACE.
TACE combined with laser therapy is an effective means of palliative treatment for large hepatocellular carcinoma. Laser therapy can be used to further treat tumor margins where embolization is unsatisfactory, and the number of treatments can be reduced.
Pacella et al. reported that TACE combined with percutaneous laser treatment for 30 cases of hepatocellular carcinoma showed that 90% (27/30 cases) of the hepatocellular carcinomas were necrotic, 93% (25/27 cases) showed shrinking or stable hepatocellular carcinomas on CT, and all cases with elevated AFP before treatment were reduced to normal after surgery, and the local recurrence rate was 7% at 1, 2, and 3 years. In the small hepatocellular carcinoma group, 100% (15/15 cases) had complete necrosis and no local recurrence, and the cumulative survival rates at 1, 2 and 3 years were 92%, 68% and 40%, respectively.
TACE combined with high-intensity focused ultrasound (TACE+HIFU) TACE+HIFU treatment can play a synergistic effect, based on TACE interrupting the blood supply to the center of the tumor, HIFU acts simultaneously on the center and periphery of the tumor, thus causing the death of all tumor cells. At the same time, HIFU can also stimulate iodine oil to generate high temperature to achieve local destruction of treatment. Preliminary results of studies have shown that TACE combined with HIFU for liver cancer treatment can increase the tumor necrosis rate and improve the quality of life of patients compared with TACE alone.
TACE combined with three-dimensional conformal radiation therapy (3-DCRT) has rarely been used in the treatment of liver cancer due to the poor radiation tolerance of the liver (tolerated dose of whole liver irradiation <35cy). In the last decade, with the development of imaging, especially the application of 3-dcrt, several clinical studies have now confirmed its safe and effective treatment of hepatocellular carcinoma. 3-dcrt, combined with tace, can overcome the shortcomings of tace and take advantage of 3-dcrt's precise localization, accurate positioning, and precise treatment to perform further treatment on the margins of embolization and/or tumors that are unsatisfactory. This approach has been reported in the literature to achieve better efficacy in the treatment of hepatocellular carcinoma and and portal vein cancer embolization.
TACE combined with proton radiotherapy, as a positively charged particle, enters the body at a very high speed, which has a very low chance of interacting with normal tissues or cells in the body due to its high speed. and effectively protect normal tissues at the same time. Because of the characteristics of proton therapy, such as strong penetration performance, good dose distribution, high local dose, less backscattering and small penumbra, especially for the treatment of tumors surrounded by important tissues and organs, it shows greater superiority.
Forty-six patients with hepatocellular carcinoma combined with portal vein eurycoma were treated with combined interventional embolization chemotherapy and proton therapy, and the proton radiation therapy was divided and alternated with interventional therapy to evaluate the recent efficacy, radiation response, and follow-up survival rate. The results showed that the effective rate was 91.3%, and the disappearance rate of portal vein cancer thrombus was 45.6%. the survival rates at 1, 6 months, 1 and 2 years were 100%, 89.1%, 52.2% and 21.4%, respectively. The median survival was 17.6 months. Interventional combined with proton radiation therapy is a new safe and effective method for patients with advanced hepatocellular carcinoma combined with portal vein thrombosis, but it still needs to be confirmed in a large sample randomized double-blind controlled trial.