Primary liver cancer is a common malignant tumor with an annual incidence of more than 600,000 worldwide. China accounts for about 50% of the global incidence and ranks second after lung cancer in tumor-related deaths, posing a serious threat to the health of our people. In recent years, more and more small hepatocellular carcinomas (tumor diameter ≤5.0 cm) have been detected thanks to the gradual popularization of AFP and B-ultrasound screening in high-risk groups. Nowadays, with the advancement of treatment, the treatment of small hepatocellular carcinoma has evolved from “single surgical resection” to a new pattern of “three-pronged treatment of surgical resection, liver transplantation and local ablation, and multidisciplinary combined treatment”. Nevertheless, studies have shown that the 5-year survival rate of small hepatocellular carcinoma has not improved significantly in the past 40 years. Now, we would like to discuss our views on this issue for reference only.
1.Radical treatment methods.
(1) Surgical resection.
Surgical resection is still the preferred treatment for small hepatocellular carcinoma and is an important way for patients to obtain long-term survival. The 5-year survival rate of 1,068 cases of small hepatocellular carcinoma after surgical resection is 62.7% and the 10-year survival rate is 46.3% in the Institute of Liver Cancer of Fudan University. At present, it is considered that liver function Child-Pugh grade A, not accompanied by severe portal hypertension and good liver reserve function are the best indications for hepatic resection of small hepatocellular carcinoma; small hepatocellular carcinoma with liver function Child-Pugh grade B is optional, but adequate preoperative preparation is needed to improve liver function as much as possible to make it reach Child-Pugh grade A; liver function Child Pugh grade C is a contraindication to hepatic resection. Theoretically, anatomical hepatectomy can remove the tumor and intrahepatic spread of micrometastases at the same time and reduce postoperative recurrence, and also reduce the possible shedding of cancer cells and intrahepatic spread and distant metastasis caused by intraoperative operation and squeezing of the tumor. Compared with anatomical hepatectomy, the long-term efficacy, long-term survival rate and tumor-free survival rate of non-anatomical hepatectomy are still inferior to those of anatomical hepatectomy, although the recent efficacy and death rate are not statistically significant. Since about 85% of patients with hepatocellular carcinoma in China have post-hepatitis cirrhosis, preoperative evaluation should be made based on tumor size, location, liver function reserve and patient’s general condition to decide whether to choose anatomical hepatectomy. For patients with good liver reserve function, anatomical resection should be preferred; for patients with poor liver reserve function, non-anatomical local resection should be performed to avoid postoperative liver failure.
The surgical resection of small hepatocellular carcinoma also includes the concept of “resection after reduction of unresectable hepatocellular carcinoma”. For some unresectable large hepatocellular carcinoma, hepatic artery ligation, intervention and freezing can be used to change the size of hepatocellular carcinoma from large to small and unresectable. Studies have shown that small hepatocellular carcinoma, regardless of the route of acquisition, has a better prognosis if it can be surgically resected.
Since its first report in 1991, laparoscopic hepatectomy has gradually expanded its application. Compared with traditional open surgery, laparoscopic surgery has the advantages of less trauma, less pain, faster recovery, and cosmetic incision. The key to laparoscopic liver resection is to select the indications strictly, keeping in mind “minimally invasive and safe”. The location of the tumor and its anatomical relationship with the important blood vessels and bile duct system of the liver are more important than the diameter of the tumor. Overall, laparoscopic hepatectomy is still in its initial stage and cannot completely replace traditional open surgery. The main reasons are that the liver is rich in blood flow and there are difficulties in controlling hemorrhage under laparoscopy, and once the main hepatic vein is torn during surgery, there are still concerns about air embolism.
(2) Liver transplantation.
Liver transplantation is the best indication for patients with small hepatocellular carcinoma with severe cirrhosis or severe loss of liver function. The 5-year survival rate of liver transplantation for small hepatocellular carcinoma is higher or similar to that of radical hepatectomy, but liver transplantation is superior to hepatectomy in terms of tumor-free survival and quality of survival. Compared with surgical resection, liver transplantation not only removes the tumor but also the sclerotic liver, thus eliminating the soil for tumor growth and solving the problem of multicenter origin of liver cancer. However, due to the shortage and high cost of donor livers, liver transplantation is only suitable for small hepatocellular carcinomas that are not suitable for surgical resection. The best choice for liver transplantation is the famous “Milan Criteria”. Taking into account the specific situation of China, scholars in China have cautiously expanded the indications of Milan criteria, and the introduction of “Fudan criteria”, “Hangzhou criteria”, “Chengdu criteria”, etc. have benefited liver cancer patients to a certain extent. The introduction of “Fudan Standard”, “Hangzhou Standard” and “Chengdu Standard” have benefited patients with liver cancer to some extent. The advent of living liver transplantation has alleviated the shortage of donor livers and enabled some liver cancer patients to receive liver donations in a timely manner, which is of special significance for liver transplantation in small liver cancers. Decision analysis of small liver cancers also suggests that liver transplantation can significantly improve survival as long as the organ waiting period does not exceed 6 to 10 months. Radiofrequency ablation or hepatic artery embolization chemotherapy (TACE) for small hepatocellular carcinoma during the waiting period for donor liver can inhibit tumor progression and provide an opportunity for subsequent liver transplantation.
(3) Radiofrequency ablation (RFA) versus microwave ablation (MWA).
Since Rossi first used radiofrequency ablation (RFA) to treat liver cancer in 1993, the application of RFA has gradually become popular. Currently, RFA is considered as one of the radical treatments for small hepatocellular carcinoma after surgical resection and liver transplantation. A multicenter prospective clinical study conducted by Livraghi et al. confirmed that the 5-year survival rate of resectable small hepatocellular carcinoma treated with RFA was 68.5%, which was higher than that of surgery. In a multicenter prospective clinical study conducted by Livraghi et al. Therefore, it is believed that RFA can replace surgical resection for small hepatocellular carcinoma ≤2.0 cm in diameter. The results of an RCT study reported by Chen Minshan et al. in China also showed that there was no significant difference in the 3-year survival rate between the surgical resection group and the RFA group. Compared with surgical resection, RFA has the following advantages.
(i) Less trauma, less reaction, significantly lower hospitalization time, complication rate and mortality than surgical resection;
②High safety, the incidence of complications after RFA in 2320 patients was summarized in a foreign report, and the incidence of serious complications was 2.2%, and the incidence of minor complications was only 4.7%;
(3) It can be repeatedly treated several times, and has its advantages for multiple and recurrent small hepatocellular carcinomas.
However, Hasegawa et al. reported that 2,857 cases of small hepatocellular carcinoma were treated by surgical resection and 3,022 cases by RFA, and the results suggested that the 2-year survival rate of the two groups was similar, but the recurrence rate of the surgical resection group was significantly lower than the RFA group. In a domestic RCT comparing the effect of surgical resection and RFA in the treatment of small hepatocellular carcinoma, there was no statistically significant difference in the 3-year survival rate between the two groups, but the 3-year tumor-free survival rate in the surgical resection group was higher than that in the RFA group, and the local recurrence rate was lower than that in the RFA group. This finding was also confirmed in the related Meta-analysis. This may be due to the fact that RFA mainly treats the lesions visible on imaging, which leads to residual microscopic lesions or neglects some satellite foci, while surgical resection can completely remove the tumor lesions while removing microscopic cancer foci metastasized along the portal branches of the tumor. Meanwhile, RFA has problems such as incomplete ablation, high local recurrence rate and inaccurate postoperative imaging assessment.
MWA is another thermal ablation technique. Both retrospective analysis and RCT studies have shown that there is no significant difference between MWA and RFA for the treatment of small hepatocellular carcinoma in terms of local efficacy, complication rate and long-term survival rate.
In clinical practice, the choice of surgical resection or RFA or MWA should be based on the patient’s liver function and constitution, the size, number and location of the tumor. Percutaneous RFA or MWA is the most minimally invasive route, but for small hepatocellular carcinoma with poor liver reserve function and tumor located on the surface of the liver, RFA or MWA can be performed laparoscopically, and only a few small hepatocellular carcinomas in special areas need open RFA or MWA.
2. Palliative local treatment methods.
(1) Intratumoral anhydrous alcohol injection (PEI).
PEI is the earliest applied local ablation technique. Studies have shown that the 1-year, 2-year and 3-year survival rates of PEI for small hepatocellular carcinoma are 98.10%, 82.04% and 53.00% respectively, which are close to the effect of surgical resection. Recently, in order to overcome the shortcomings of traditional PEI that it is difficult to disperse alcohol evenly in the tumor and requires repeated treatment, the improved “multi-pole alcohol injection needle” contains a retractable sub-needle with a diameter of up to 5 cm when the sub-needle is fully opened, which is conducive to the uniform distribution of alcohol in the tumor. With this technology, the complete ablation rate of small hepatocellular carcinoma can reach 95% in the First Hospital of Sun Yat-sen University. This method is especially suitable for patients with small hepatocellular carcinoma who refuse to adopt radical treatment means for economic reasons.
(2) Transcatheter arterial chemoembolization (TACE ).
TACE, for patients with small hepatocellular carcinoma that cannot be surgically resected, can be an option and has been widely used in the clinic. However, RCT studies have demonstrated that conventional TACE does not prolong patient survival, probably because its efficacy is limited by the blood supply to the tumor arteries, making it difficult to completely kill cancer cells. The method of “super-selective cannulation and segmental embolization” can fill the tumor lesion with iodine oil to completely block the blood supply of hepatic artery, and make the iodine oil penetrate into the small branches of portal vein around the tumor to block the blood supply of portal vein around the tumor, so as to achieve the purpose of double embolization of hepatic artery and portal vein; meanwhile, the non-tumor tissue can be protected.
(3) High-intensity focused ultrasound (HIFU) and three-dimensional conformal radiotherapy (3DCRT).
HIFU is mainly used to produce high thermal and cavitation effects by using high energy in the focus area of ultrasound to cause coagulative necrosis of tumor tissues in the target area (i.e. treatment area). Three-dimensional conformal radiotherapy (3DCRT) uses stereotactic technology to precisely locate the target area (small hepatocellular carcinoma), and to develop the number and angle of fields according to the three-dimensional treatment plan. Both are palliative treatments. However, both of them are palliative treatments, and there are many objective and subjective factors affecting the efficacy, so the author believes that they can only be considered for a very small number of small liver cancer patients who are not suitable for or refuse other radical treatments.
(4) Cryotherapy.
It adopts argon-helium targeted tumor cryoablation technique, which can rapidly chill cancer tissues to below -160℃ and then re-temperature to 20-40℃ by helium targeting, which can directly cause dehydration and rupture of cancer cells; or destroy small blood vessels of tumor and cause ischemia and hypoxia, resulting in death of cancer cells. Since its clinical application in small hepatocellular carcinoma is far less common than RFA or MWA, more experience has to be accumulated before it can be reasonably evaluated.
3. Combined sequential therapy.
One of the principles of standardized treatment for hepatocellular carcinoma is combination therapy, and the combined use of multiple treatment modalities can help improve the efficacy.
In recent years, some scholars have combined RFA and PEI in the treatment of small hepatocellular carcinoma. The reasons for the increased effectiveness were: RFA could heat the injected anhydrous ethanol and improve the therapeutic effect of anhydrous ethanol; PEI embolized small vessels and reduced the heat loss effect caused by blood flow; anhydrous ethanol could diffuse to the leaky site of RFA and also to the periphery of RFA ablation range, thus reaching a more effective safety boundary.
The combination of RFA with segmental arterial embolization chemotherapy has also been reported more frequently, with increased efficacy in the combination group. The increase in efficacy may be attributed to the fact that the abundant blood flow around the hepatocellular carcinoma in RFA alone takes away some of the heat and reduces the extent of ablation.
TACE combined with PEI treatment has also been reported. after TACE embolization of the hepatic artery blood supply, the tumor is partially necrotic, the blood supply of the tumor is obviously reduced, the parenchyma is loosened and the interval is destroyed, which is conducive to the diffusion of anhydrous ethanol in the tumor and reduces the washout and shunt of anhydrous ethanol.
4.Systemic treatment.
Liver cancer is a systemic disease, so small liver cancer patients need timely antiviral treatment according to the specific condition of hepatitis virus infection after surgery. In addition, traditional Chinese medicine and biological immunotherapy as adjuvant therapies are helpful to enhance patients’ immunity, improve related symptoms, improve survival quality and delay tumor recurrence. As for molecular targeted therapies such as sorafenib, which is the only multi-targeted molecular targeted drug proven to be effective in the treatment of liver cancer, its main indication is intermediate to advanced liver cancer. Small hepatocellular carcinoma is not equal to early hepatocellular carcinoma, and it can be considered for patients with small hepatocellular carcinoma with vascular infiltration or intravascular thrombosis after surgery, but more research and studies are needed.
In conclusion, the selection of treatment for small hepatocellular carcinoma is a scientific and dialectical clinical decision-making process, which requires comprehensive consideration based on the patient’s general condition and liver reserve function, the size, number and location of the tumor, the technical strength of the unit and the patient’s willingness to develop the best individualized treatment plan for the patient.
Generally speaking, for small hepatocellular carcinoma patients with good liver function, surgical resection is still the first treatment option; for patients with combined cirrhosis and deep tumor site, especially in the center of the right liver, RFA or MWA can be the first treatment option due to the high risk of surgery and the difficulty to ensure sufficient margins; for patients with severe cirrhosis and liver function loss, liver transplantation is the best treatment option. At the same time, we need to pay attention to the scientific combined application of various treatment methods to make the treatment of small liver cancer more standardized and standardized, so as to achieve another leap in the efficacy of small liver cancer. However, the real improvement or breakthrough of the treatment effect of small liver cancer may depend on the further deepening and elucidation of basic research on liver cancer, especially on the mechanism of recurrence and metastasis.