I. Current status of ablation therapy for liver cancer at home and abroad
In recent years, ablation technology under the guidance of imaging has played an important role in the treatment of liver cancer, among which, especially local ablation therapy represented by radiofrequcncyablation (RFA) and microwave ablation has made a breakthrough in the treatment effect of liver cancer because of its advantages such as less invasive, easy to operate and effective coagulation and inactivation of tumor. The 2008 edition of the National Comprehensive Cancer Network (NCCN) and the Japanese Society of Surgery clinical practice guidelines for hepatocellular carcinoma have identified RFA as one of the important treatment tools for liver cancer along with surgery and liver transplantation; Chinese liver cancer experts academician Tang Zhaoyou and academician Wu Mengchao advocated ablation treatment for liver cancer at the National Cancer Conference as early as 2002 and began to hold symposiums in 2006.
Most of the literature at home and abroad reported that RFA is only effective for inactivating small hepatocellular carcinoma, and the necrosis rate is only 48%~56% for tumors >3,0cm. Due to the limitation of ablation thermal field area. For tumors in dangerous areas adjacent to important organ structures and vascular-rich tumors, RFA is prone to recurrence and has a high complication rate after treatment; many factors affect the efficacy of RFA and its application.
Currently, most of the ablation therapy-guided puncture techniques used in Asian and European countries are ultrasound or ultrasound fusion navigation techniques, conlrast-enhanced ultrasound (CEUS), color Doppler ultrasound and other related techniques, and CT/MR guidance is also used, mainly in the United States and European countries. Ultrasound-guided percutaneous RFA treatment can be performed mostly in outpatient treatment rooms or operating rooms; through ultrasound multi-sectional scanning, three-dimensional localization can be performed and overall overlapping ablation can be guided; the puncture route can be chosen flexibly and the needle can be guided to avoid important vascular structures; the needle depth and relationship with adjacent organs can be observed in real time from multiple angles; the ablation treatment process can be monitored in real time, complications such as bleeding can be detected sensitively and ablation can be guided to stop bleeding. The precise ablation under the guidance of ultrasound can reduce the damage to normal liver tissue. Local ablation treatment is light in liver function and quick in body recovery, and generally does not cause intrahepatic dissemination and metastasis; it is feasible to re-treat newly generated recurrent cancer for many times. Ultrasound-guided ablation also has the advantages of no radiation, low cost and easy operation, which plays an important role in the treatment of focal hepatocellular carcinoma and recurrent carcinoma, so this technology is gradually recognized by physicians and patients.
Domestic treatment progress
1. RFA treatment for refractory tumors. The annual incidence rate of liver cancer in China is high, and there are many large tumors at the time of consultation, many of them are in the middle and late stages, and most of them are combined with cirrhosis, and about 70% of them have lost the chance of surgical resection. For these refractory hepatocellular carcinomas, our center uses the following additional protocol strategies.
Improving the outcome of large tumor treatment. For large tumors, a multifocal overlap calculation scheme is used to effectively inactivate the largest range of tumors with the fewest ablation foci. The basic elements include calculation of the number of ablation foci, ablation localization pattern and reasonable ablation procedure. It is easy to obtain overall inactivation by ablating large tumors under image guidance according to this protocol. In recent years, a new multi-needle double-electrode cold circulation ablation system can lay 2~3 electrode needles according to the size and shape of tumor, and the current alternately circulates in convection between the effective distance electrodes to complete the conformal coagulation ablation of large tumors. In a multicenter joint study, intraoperative RFA or intraoperative RFA after transarterial cannulation chemoembolizatiort (TACE) was performed for large tumors that are difficult to inactivate by percutaneous ablation, difficult to resect by surgery or prone to inadequate liver reserve function after resection, and the preliminary treatment results confirmed its safety and effectiveness; it has also been reported that RFA combined with anhydrous ethanol injection can effectively treat ≤7,0 cm hepatocellular carcinoma.
Individualized treatment of special site tumors. For tumors located in the adjacent gallbladder, intestinal duct and diaphragm that cannot be resected surgically, about 40% of patients require percutaneous RFA treatment, and individualized regimens are needed for these sites. Broadly speaking, the appropriate strategies used include local water injection to separate the liver from the surrounding structures in the tumor area, designing needle placement schemes for adjacent tumors, and techniques such as lifting and expanding needles to improve inactivation rates and reduce burn injuries to surrounding organs. Intraoperative or laparoscopic RFA, when available, facilitates proper treatment of these tumors as well as large tumors on the liver surface.
Treatment strategy for blood-rich tumors. The use of TACE 1~2 times to control the tumor blood supply can improve the efficacy of RFA; for refractory tumors with unsatisfactory TACE effect and still rich blood supply, they are prone to recurrence and metastasis. For refractory tumors with satisfactory TACE effect and rich blood supply, which are prone to recurrence and metastasis, RFA can be performed by firstly using small ball foci with high energy to the area where color Doppler ultrasound shows that the tumor vessels are penetrating into the tumor, and then performing multi-ball foci “base-plus-coagulation” to perform RFA immediately under the tumor ischemia.
The above mentioned refractory hepatocellular carcinoma has been proven to be effective. The inactivation rate of adjacent gallbladder tumor foci was 93.5% (58/62), 92.5% (123/133) for adjacent diaphragm, 92.4% (61/66) for adjacent intestinal canal, and 93.2% (68/73) for adjacent large blood vessels.
2. Feasibility of RFA treatment for mid- to late-stage hepatocellular carcinoma. It is a difficult problem in clinical treatment in China because of its easy to spread and poor liver function, and the feasibility of RFA treatment is a hot spot to be studied. In our center, for some of these patients, a reasonable combined treatment mode is determined according to tumor biological behavior and patient’s condition before treatment, such as palliative RFA after one to two TACE sessions for multiple tumors and large tumors with rich blood supply; the feasibility of tumor ablation and inactivation is fully evaluated before RFA, and regular hepatoprotective treatment is performed; during treatment, the established protocol and measures are taken to achieve adequate ablation and reduce the damage to liver tissue and large blood vessels. After treatment, liver preservation therapy and anti-viral therapy are adopted from Chinese and Western medicine; in parallel, a series of active measures such as active follow-up, early diagnosis of recurrent metastases and timely re-ablation are taken. The average size of tumor was 4.5cm, with multiple cases (34%) and 36% of liver function grade B and C. The early inactivation of tumor after RFA was 90.9% (120/132), with 2 cases (2.2%) of serious complications and no related deaths; the follow-up period was 3~129 months. At 129 months of follow-up, the recurrence rate of local lesions was 15,2% (20/132), and the overall survival rates at 1, 3 and 5 years were 83,3%, 48,3% and 21,9%, respectively, with a median survival of 35 months. The treatment results confirm that RFA can effectively prolong the survival of some patients with intermediate to advanced liver cancer.
In our center, a group of liver cancer patients who lost the opportunity of surgery, TACE and liver transplantation, 13 cases (17 foci) of liver function Child-Pugh grade C were treated with palliative RFA, and the 1-, 2- and 3-year survival rates were 53, 8%, 30, 8%, 15, 4%, respectively, but the complication rate was high, amounting to 13, 6% (3/22), and one patient with >5, 0 cm diameter HCC co-infection after RFA and died of liver failure 2 months later.
The efficacy of RFA in the treatment of recurrent cancer after surgical resection has been confirmed. In a group of postoperative recurrent cancer patients (103 cases) in our center, the survival rates of 1, 3 and 5 years in the RFA combined with TACE treatment group were 88, 5%, 64, 6%, 44, 3% respectively, which were slightly higher than those in the RFA treatment group alone (73, 9%, 51, 1%, 28, 0%), but the difference was not statistically significant; the efficacy of the combined treatment group was significantly higher than that of the TACE treatment group alone (65, 8%, 38, 9%, 19, 5%). (38, 9%, 19, 5%).
RFA as an optional method of targeted treatment or local treatment for liver transplant patients in the liver waiting period not only achieves successful liver transplantation but also reduces the recurrence rate and prolongs tumor-free survival. For recurrence after liver transplantation, due to good liver function and large volume, it is worthwhile to pay attention to follow-up and early diagnosis, and feasible multiple RFA retreatment.
III. Existing problems
The promotion of RFA treatment for liver cancer in China has many problems as follows.
1. The access system is not clear. At present, RFA and microwave ablation and other ablation techniques are being actively promoted and carried out in Chinese clinics, and the operators come from many disciplines, including surgery, oncology or gastroenterology, as well as interventional medicine, imaging (radiology CT) or ultrasound. To master this new technology, as clinical medical-surgical and interventional physicians, they need to pay attention to the skills of imaging to determine the size and scope of tumor and image-guided interventional puncture; in particular, they need to judge the biological behavior of tumor to select the indications; while imaging physicians need to pay attention to fully evaluate the liver function and systemic condition of patients, select the indications and appropriate combined treatment mode for interventional treatment. In summary, successful ablation treatment should integrate the strengths and thinking concepts of clinical and imaging physicians, how to unify and popularize, and determine the access system of treatment as early as possible.
2. Insufficient attention is paid to image-guided ablation. Those who choose percutaneous ablation therapy and meet the basic conditions of treatment should first understand the local situation of tumor through adequate imaging means (CEUS, enhanced CT, MRI), such as the number and characterization of tumor, the presence of subfoci, whether the morphological boundary is clear and definite, the scope of infiltration, etc. It is especially necessary to confirm the relationship between tumor and large blood vessels and surrounding organs, so as to set the purpose of treatment; formulate the treatment plan, ablation procedure, cloth In addition, it is necessary to confirm the relationship between the tumor and large blood vessels and surrounding organs, so as to set the treatment purpose, formulate the treatment plan, ablation procedure, needle positioning and puncture route, and select the corresponding additional methods and strategies. At present, the application of new CEUS technology confirms that it can make judgment on the biological force and infiltration range of tumor, thus playing an important role in RFA treatment.
3.Lack of formal technical training institutions. At present, more than one hundred hospitals in China have carried out tumor ablation treatment methods, but in view of the large differences in operation technology level, treatment experience, instruments and equipment and patients’ degree of disease, the treatment effect varies, and the recurrence rate and complication rate are high. As a new technology and a new discipline requiring multidisciplinary participation, the current promotion is only limited to lectures and observation of surgery organized by various hospitals or a certain society, which can be described as “slapdash”. Standardized treatment technology training is a problem that needs to be paid attention to and solved by the relevant government health departments, which is especially urgent in line with China’s national conditions.
4. It is necessary to establish a guideline in line with the national situation. The majority of patients cannot be surgically resected due to poor liver reserve function and non-small hepatocellular carcinoma, so the scope of RFA indications for Chinese hepatocellular carcinoma patients may be wider than that of foreign countries. On the basis of comprehensive literature, domestic experts organized by the Liver Cancer Collaborative Group of the Anti-Cancer Society and the Medical Secretary of the Ministry of Health have discussed for many times, and had first proposed the indications: ≤3 cancer foci, the largest foci ≤3,0cm can obtain local radical efficacy; single lack of blood supply liver cancer ≤5,0cm in diameter (including recurrent cancer one year after surgical resection) can also obtain inactivation effect by using multifocal overlapping ablation scheme and strategy. The authors believe that in China, local ablation can be relaxed to ≤6,0cm focal tumor with clear envelope or boundary and sufficient safety range around the tumor; liver function Child-Pugh grade A or partial grade B, without extrahepatic metastasis; however, the premise is that the operator should be trained.
The above “Chinese standard” is not yet supported by the results of multicenter prospective studies, and technical training is urgently needed to achieve this goal on the basis of popularization and improvement.
5. Lack of optimal RFA treatment concept. This includes screening for appropriate indications, setting ablation protocol strategies, and accurate needle placement techniques to achieve precise and conformal tumor inactivation, i.e., treating RFA treatment as the primary means of tumor inactivation (rather than a complementary means that is ineffective or inefficient after various other treatments). However, not pursuing the best ablation treatment effect is a more common phenomenon in clinical practice nowadays.
Prospects
Image-guided minimally invasive ablation technology for liver cancer treatment is effective, low cost and fast recovery, which not only prolongs the survival period of many patients and obtains good vital signs and quality of life, but also enhances patients’ confidence in curing the disease with feasible repeated treatments. With the development of treatment technology, the number of patients receiving this treatment has increased, and the application prospect is broad in China. The emphasis on precise ablation and intraoperative real-time monitoring under the guidance of various imaging technologies and the development of standardized RFA protocols can improve the efficacy and expand the scope of application for non-surgical liver cancer and postoperative recurrent cancer. Clinical studies have confirmed that with the mastery of ablation treatment, new ablation techniques such as eryo-ablation, laser ablation, chemo-ablation, irreversible electroporation, particle implantation and brachytherapy have been developed and applied. (1), particle implantation (brachytherapy), biotherapy (biotherapy), photodynamic (photo-dymmic), highintensityfocusedullrasound (highintensityfocusedullrasound) therapy, etc. are beginning to be applied in clinical research. In recent years, the development of medical image guidance technology will enable more accurate targeting and faster and better ablation effects, thus playing an important role in the comprehensive treatment of liver cancer.
The development direction of RFA needs to focus on promoting the establishment of standardized combined treatment mode. For non-surgical hepatocellular carcinoma with unclear boundary, >5,0 cm or multicenter origin, it is more important to combine with surgery and intervention to perform comprehensive treatment: for example, surgical resection combined with local ablation to reduce the damage of non-tumor-bearing liver tissue; for arsenical carcinoma with rich blood supply, 1~2 times TACE to reduce the effect of “heat deposition effect”, improve the inactivation of RFA and reduce the number of TACE. The effect of RFA inactivation can be improved and the number of TACE can be reduced. In recent years, RFA combined with thermosensitive liposome chemotherapy has been gradually shown to be effective, as intravenous injection of adriamycin can concentrate in the liver, and immediate ablation can release adriamycin wrapped in liposomes locally into the tumor, thus effectively exerting anti-tumor effects. The authors’ application results confirmed that it can improve the inactivation efficiency of large tumors.
Surgical resection combined with ablation therapy or intraoperative ablation of tumors that are not easily resectable is a technique that cannot be ignored to improve the efficacy of hepatocellular carcinoma. However, intraoperative guided puncture localization technique is not yet mature and popular. For this reason, training surgeons on ultrasound scanning and intraoperative scanning and puncture techniques is a necessary skill base, and early implementation of the project by relevant departments will promote this technique more deeply and effectively.
In order to standardize the clinical application of tumor ablation therapy technology, ensure medical quality and medical safety, and serve tumor patients more effectively, the health management department needs to set up an expert working group on ablation therapy guideline, formulate the management specification of tumor ablation therapy technology and technical guideline training syllabus, and establish an ablation therapy training center. On this basis, multi-center research should be organized to establish a minimally invasive ablation treatment model for liver cancer that is consistent with national conditions and easy to be applied by applying evidence-based medical results.