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 (tumors ≤5.0 cm in diameter) have been detected thanks to the gradual popularization of AFP and B-ultrasound screening in high-risk groups. Currently, with the advances in treatment, the treatment of small hepatocellular carcinoma has evolved from a “single surgical resection” to a “triad of surgical resection, liver transplantation and local ablation therapy, 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, so there are still many debates on how to choose the reasonable and correct treatment for small hepatocellular carcinoma in clinical practice, and more clinical studies and explorations are needed to provide the basis for the choice. Now we would like to discuss our views on this issue for reference only.
1.Radical treatment methods
1. 1.Surgical resection
Surgical resection is still the first choice of 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 Liver Cancer Institute of Fudan University. At present, it is considered that the best indication for hepatic resection of small hepatocellular carcinoma is Child-Pugh grade A liver function, not accompanied by severe portal hypertension and good liver reserve function; small hepatocellular carcinoma with Child-Pugh grade B liver function is an option, but adequate preoperative preparation is needed to improve liver function as much as possible to reach Child-Pugh grade A; Child-Pugh grade C liver function is a contraindication for hepatic resection. is a contraindication to hepatic resection. Theoretically, anatomical hepatectomy can remove the tumor and intrahepatic spread of micrometastases at the same time, reduce postoperative recurrence, and also reduce the possible shedding of cancer cells and intrahepatic spread and distant metastasis caused by intraoperative manipulation 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 cryotherapy can be used to change the size of hepatocellular carcinoma from large to small and unresectable to resectable. 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, and small hepatocellular carcinoma located in the peripheral area of the liver is a good indication for laparoscopic hepatectomy. In general, 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 it is difficult to control hemorrhage under laparoscopy, and once the main hepatic vein is torn during surgery, there is still the concern of air embolism; secondly, the laparoscopic surgeon cannot touch the liver directly, so it is difficult to estimate the liver cut edge accurately, and there is concern about whether the requirement of radical cure can be achieved.
1.2. 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. In 1996, Mazzaferro proposed that small hepatocellular carcinoma with a single tumor diameter of ≤5 cm or no more than 3 tumors and a maximum tumor diameter of ≤3 cm, with severe cirrhosis, no vascular invasion, and no extrahepatic metastasis is the best choice for liver transplantation. The best choice for liver transplantation is the famous “Milan Criteria”. In the light of China’s specific situation, Chinese scholars have cautiously expanded the indications of Milan criteria, and the introduction of “Fudan criteria”, “Hangzhou criteria” and “Chengdu criteria” 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 patients with liver cancer to receive liver donations in a timely manner, which is of special significance for liver transplantation in small liver cancer. 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. The use of radiofrequency ablation or hepatic artery embolization chemotherapy (TACE) for small hepatocellular carcinoma during the donor waiting period may inhibit tumor progression and provide an opportunity for subsequent liver transplantation.
1.3, Radiofrequency ablation (RFA) versus microwave ablation (MWA)
Since Rossi first used radiofrequency ablation (RFA) to treat liver cancer in 1993, the use of RFA has gradually gained popularity. Nowadays, RFA has been 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, RFA is considered to be an alternative to 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: (1) it is less traumatic and less reactive, and the length of hospitalization, complication rate and mortality rate are significantly lower than those of surgical resection; (2) it is safe, and the complication rate of 2320 patients after RFA treatment was summarized in a foreign report, and the incidence of serious complications was 2.2% and that of minor complications was only 4.7%; (3) it can be repeatedly treated for many times, and has advantages for multiple and recurrent small hepatocellular carcinomas. However, Hasegawa et al.
However, Hasegawa et al. reported that surgical resection and RFA treated 2857 and 3022 cases of small hepatocellular carcinoma, respectively, and the results suggested that the 2-year survival rates of the two groups were similar, but the recurrence rate of the surgical resection group was significantly lower than that of the RFA group. In a domestic RCT comparing the effect of surgical resection and RFA in the treatment of small hepatocellular carcinoma, the 3-year survival rate of the two groups was not statistically significant, but the 3-year tumor-free survival rate of the surgical resection group was higher than that of the RFA group, and the local recurrence rate of the tumor was lower than that of the RFA group. This finding was also confirmed in the related Meta-analysis. This may be due to the fact that RFA is mainly performed on imaging lesions, resulting in residual microscopic lesions or neglected satellite foci, whereas surgical resection can completely remove tumor lesions while removing microscopic cancer foci metastasizing 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, etc. Especially for small hepatocellular carcinoma in the central region of the right liver with a tumor diameter of ≤3 cm, RFA or MWA can be an alternative to surgical resection. 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 locations need open RFA or MWA.
2. Palliative local treatment methods
2.1. 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. PEI has the advantages of less complications, simple operation and low cost in treating small hepatocellular carcinoma. 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 Affiliated Hospital of Sun Yat-sen University. This method is especially suitable for patients with small hepatocellular carcinoma who refuse to adopt radical treatment means due to economic reasons.
2.2. Transcatheter arterial chemoembolization (TACE)
TACE is an option for patients with small hepatocellular carcinoma that cannot be surgically resected and has been widely used in clinical practice. 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, which makes 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 tissues can be protected.
2.3.High-intensity focused ultrasound (HIFU) and three-dimensional conformal radiotherapy (3DCRT)
HIFU mainly uses the high energy in the focus area of ultrasound to produce high thermal and cavitation effects to cause coagulative necrosis of the tumor tissue 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 the number and angle of the fields are set according to the three-dimensional treatment plan, and the tumor is irradiated by multiple non-coplanar arc-shaped fields, so as to increase the irradiation dose to the target area, while the dose to the peripheral area of the tumor is sharply reduced in a gradient, thus reducing the damage to the surrounding normal liver tissue and increasing the local control rate of the tumor. Both are palliative treatments. However, both of them are palliative treatments, and there are many objective and subjective factors affecting the efficacy. Therefore, the author believes that they can be considered only for a very small number of patients with small hepatocellular carcinoma who are not suitable for or refuse other radical treatments.
2.4. Cryotherapy
Currently, argon-helium targeted tumor cryoablation technique is more commonly used, using argon-targeted refrigeration to rapidly chill cancer tissues to below -160℃, and then re-tempering 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 cancer cell death. Since its clinical application in small hepatocellular carcinoma is far less common than RFA or MWA, more experience has yet 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, and the combined group is better than the RFA group alone in terms of complete tumor ablation rate, local recurrence rate, recurrence time and postoperative survival rate. 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 hepatocellular carcinoma in RFA alone takes away some of the heat and reduces the extent of ablation, while hepatic artery chemoembolization reduces the blood flow and therefore increases the extent of tumor ablation.
TACE combined with PEI treatment has also been reported. after TACE embolization of hepatic artery blood supply, the tumor is partially necrotic, the blood supply of the tumor is obviously reduced, the parenchyma is loosened and the septum is destroyed, which is conducive to the diffusion of anhydrous ethanol in the tumor and reduces the flushing and shunting of anhydrous ethanol.
4.Systemic treatment
Liver cancer is a systemic disease, so patients with small hepatocellular carcinoma need to receive timely antiviral treatment according to the specific condition of hepatitis virus infection after surgery. In addition, traditional Chinese medicine and biological immunotherapy are helpful as adjuvant treatments to improve patients’ immunity, improve related symptoms, enhance 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.
In general, 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 guarantee 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 combination of various treatment methods to make the treatment of small hepatocellular carcinoma more standardized and standardized, so as to achieve another leap in the efficacy of small hepatocellular carcinoma. 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.