Ablation treatment of large liver cancer

Ablation treatment of large liver cancer.  Patients with large liver cancer are generally severely ill, often with severe liver cirrhosis, multiple intrahepatic lesions, or tumor vascular invasion. Only a small number of patients can tolerate surgery, and the prognosis of patients is poor.

Primary liver cancer is a common malignant tumor worldwide, its global incidence ranks sixth among all malignant tumors, and its tumor mortality rate ranks fourth [1]. Primary liver cancer is the fourth most common malignant tumor and the third leading cause of tumor death in China. Nearly half of the global cases occur in China. Primary liver cancer includes three different pathological types: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, and mixed liver cancer. Among them, HCC is the most common pathological type of primary liver cancer, accounting for 85% to 90% [2- 3], “liver cancer” in this article refers only to HCC. The prognosis of liver cancer patients is closely related to the size of the tumor. According to the tumor diameter, they can be divided into small liver cancer and large liver cancer. When the tumor diameter is greater than 5 cm, it is defined as large liver cancer. Large liver cancer has a low level of tumor differentiation and generally has a poor prognosis.

1 Current status of treatment of major liver cancer

Surgical resection is the preferred treatment for large liver cancer. The 5-year survival rate for patients with large liver cancer suitable for surgical resection can exceed 50% [4], but because large liver cancer is prone to tumor vascular infiltration, intrahepatic or extrahepatic distant metastasis, and Most patients are accompanied by severe liver cirrhosis, and only 20% to 30% of patients can receive surgical treatment [5]. Transhepatic arterial chemoembolization (TACE) is currently the treatment plan recommended by many countries’ guidelines for unresectable large liver cancer.

A number of randomized controlled studies [6-7] have confirmed that compared with palliative care, TACE can significantly improve patients with advanced liver cancer Survival rate. TACE is the direct injection of embolic agents and chemotherapeutic drugs into the blood vessels of tumors through the hepatic artery to block the blood vessels and increase the efficacy of chemotherapy, including traditional lipiodol-chemotherapeutic drug emulsion embolization and drug-loaded embolization microsphere embolization, research [8 ] It was found that the two treatment methods had no significant difference in the curative effect of liver cancer, but the postoperative complications of drug-loaded embolization microsphere embolization were relatively few.

The current study shows that a single TACE treatment of patients with large liver cancer has limited efficacy. A retrospective study of 10 108 patients with advanced liver cancer who received TACE treatment was included in 101 studies [9] showed that the 5-year survival rate of patients was only 32.4 %, the median survival time is 19.4 months. Yoon et al. [10] reported 163 patients with unresectable large liver cancer who received TACE treatment. Only 65% ​​of the patients could benefit from the treatment. The median survival time of the patients was 15.8 months, and whether they received surgery after TACE Or local ablation therapy is an important factor affecting the survival of patients.

At the same time, for patients with large liver cancer, simple TACE treatment requires a large dose of embolic materials, which damages the surrounding normal liver tissue while treating the tumor, increasing the risk of liver failure in patients with liver cancer [11-12]. In recent years, tumor ablation therapy has been widely used in the minimally invasive treatment of tumors due to its characteristics of minimally invasive, high-efficiency, and reproducible treatment, and has become the first-line treatment for early liver cancer. However, there are still many ablation treatments for large liver cancer at home and abroad. dispute.

TACE therapy alone is difficult to achieve a cure effect, and repeated treatments can easily lead to severe liver damage in patients, while ablation therapy can cooperate with TACE to further inactivate residual lesions, reduce the use of TACE embolic agents and completely cure the tumor. With tumor ablation technology In line with the development of treatment concepts, ablation has gradually become an important treatment method in the comprehensive treatment of large liver cancer, and treatment methods such as TACE combined with ablation are one of the most important treatment options for minimally invasive interventional treatment of large liver cancer in recent years.

2 Common methods and current status of ablation of large liver cancer

Tumor ablation technology uses physical or chemical methods to coagulate, necrosis, or cause tumor cell apoptosis through temperature gradient changes or chemical reactions, and inactivate the tumor tissue in situ, and then the tumor tissue is gradually absorbed and dissipated , To achieve the effect of non-surgical “resection” of tumors, with the characteristics of less trauma, good curative effect, fewer complications, short hospital stay, and low cost. Commonly used ablation treatment methods include (RFA), microwave ablation (MWA) and cryoablation, etc. .

2.1 Radio Frequency Ablation (RFA)

RFA uses high-frequency currents (>10 KHz) to vibrate and generate heat from the ions of tumor tissues, resulting in coagulation and necrosis of the tissues. RFA was applied to the ablation of large liver cancer earlier and achieved good results. Takaki et al. [13] reported that RFA combined with TACE was used to treat 20 patients with large liver cancer, each with no more than 2 tumors, and a total of 32 tumors with a diameter greater than 5 cm, through 1 ablation treatment, 20 (20/32, 63%) tumors can be completely inactivated, and the remaining tumors are completely inactivated within 3 treatments.

There were 2 cases of serious complications (1 case of liver Abscess and 1 case of diaphragmatic perforation), the 1, 3, and 5-year survival rates were 100%, 62%, and 41%, respectively, and the 1, 3, and 5-year tumor-free survival rates were 74%, 28%, and 14 %. Peng et al [14] compared and analyzed RFA combined with TACE and TACE alone in the treatment of liver cancer patients with a diameter of less than 7 cm by designing a prospective clinical trial. A total of 94 patients received RFA combined with TACE treatment, while 95 patients received only RFA treatment, RFA combined The 1, 3, and 4-year survival rates of patients in the TACE group were 92.6%, 66.6%, and 61.8%, respectively, and the tumor-free survival rates were 79.4%, 60.6%, and 54.8%, respectively, while the 1, 3, and 4-year survival rates of patients in the RFA group The survival rates were 85.3%, 59%, and 45%, respectively, and the tumor recurrence-free survival rates were 66.7%, 44.2%, and 38.9%, respectively. The combined treatment of RFA and TACE can prolong liver cancer with a diameter less than 7 cm better than RFA alone. The patient’s survival time and reduce tumor recurrence rate.

2.2 Microwave ablation (MWA)

MWA uses high-frequency electromagnetic waves to act on the tissues, causing the tissues to absorb a large amount of microwave energy to quickly generate a large amount of heat, and the tumor tissue is instantly thermally coagulated and necrotic. MWA has the advantages of large ablation range, short treatment time, and not easily affected by the heat sink effect. At the same time, because multiple microwave antennas can operate at the same time, a larger ablation range can be generated through a synergistic effect.

Compared with RFA, it is more suitable for ablation of large liver cancer. treatment. Hu et al. [15] used MWA combined with TACE to treat patients with large liver cancer with cirrhosis. A total of 84 patients were included in the study. The researchers first inactivated tumors through MWA, and TACE treatment was performed within 1 month after the operation to further kill the tumors. During the treatment, only 2 patients with bleeding required blood transfusion.

The 1, 2, and 3-year survival rates of the patients were 81%, 68%, and 49%, respectively. The 3-year local recurrence rate of tumors was 25.8%, and good results were achieved. At the same time, Hu et al. found that preoperative AFP level, Child-Pugh grade and tumor number are important factors affecting patient survival. A prospective multicenter study in Italy [16] included 215 patients with liver cancer with liver cirrhosis who received MWA treatment, of which 109 patients had only one lesion (diameter range: 5.3-8 cm) and 70 patients There are 2 lesions (diameter range: 3~6 cm), 36 patients have 3~5 lesions (diameter range: 1.5~6.8 cm). In this study, lesions with a diameter of 1.5~3.5 cm can pass once Microwave ablation treatment is completely inactivated. 89% of the 3.5~5 cm lesions can be completely inactivated by one microwave ablation treatment, but can be completely inactivated after 2 treatments. For the 5~8 cm lesions, 92% The lesion was finally completely inactivated.

During the treatment, only one patient died of hepatic tumor rupture and bleeding 20 hours after ablation, and the remaining patients had no serious complications. In this study, the 1-, 3-, and 5-year survival rates of liver cancer patients with a single tumor greater than 5 cm in diameter were 89%, 66%, and 34%, respectively. Therefore, the researchers believe that for patients with large liver cancer, transcutaneous MWA is A safe and effective treatment.

2.3 Cryoablation

Cryoablation is a treatment method that causes tumor cell disintegration and tumor microvascular rupture through rapid freezing and rapid rewarming of tumors. It also has the characteristics of providing tumor neoantigens and synergistic immunotherapy. Huang et al. [17] retrospectively analyzed 86 patients with liver cancer with a diameter greater than 4 cm who received TACE and cryoablation. The 1, 3, and 5-year survival rates of the patients were 74.5%, 38.0%, and 29.3%, respectively.

Three of the patients had serious complications (1 case of liver abscess and 2 cases of massive ascites). Wei et al. [18] compared 48 cases of TACE combined with MWA and 60 cases of TACE combined with cryoablation of large liver cancer patients. After using the propensity score matching method to analyze, the median survival time of microwave and cryo groups were 20.9 months and 13.5 months, respectively. Months (P=0.1), the incidence of complications due to ablation in the two groups were 66.7% and 88.3% (P=0.006). There was no statistical difference in the prognosis of patients with microwave and cryoablation, but there was no statistical difference in the prognosis of patients in the microwave group.

The incidence is lower than that of the frozen group. Compared with MWA and RFA treatments, cryoablation is currently less used in the comprehensive treatment of large liver cancer. However, the tumor-induced immune effect after cryoablation is significantly better than other thermal ablation treatments. With tumor immunotherapy in recent years With rapid development, cryoablation will inevitably play a more important role in the comprehensive treatment of large liver cancer [19-20].

Progress in ablation treatment of 3 major liver cancers

There are still many controversies about the curative effect of ablation therapy for large liver cancer. How to choose the appropriate ablation time, reduce the residual tumor after ablation, reduce the recurrence of the tumor after the ablation, and make the patient survival benefit is the current clinical and scientific research still need to continue to explore problem.

3.1 Timing of ablation therapy for large liver cancer

At present, there are two viewpoints in the combined treatment of TACE and ablation. One is the sequential treatment of TACE combined with ablation, that is, the treatment plan of combined ablation in a short period of time after TACE treatment. The Chinese  scholar Huang Jinhua team [21] reported a retrospective study of 43 cases of large liver cancer treated with multi-needle ablation within 3 days after TACE. In the study, three-dimensional visualization software was used to rationally plan multiple MWA antennas for the treatment of large liver cancer, 16 The tumors of 37.2% patients were completely inactivated by one treatment, and the tumors of another 19 patients (44.2%) were inactivated by more than 90% of the tumor volume.

The liver function of the patients was only 3 days after surgery. There was a short-term change and returned to normal within 1 month. The median survival time of the patient was 23.0 months, and the median progression-free survival time was 4.2 months. Large liver cancer has a rich blood supply. Although MWA can produce a large ablation range, it is inevitably affected by the effect of large blood vessel heat sink. TACE can embolize the blood vessel of the tumor. Multi-needle ablation can be performed within 1 to 3 days after surgery. Significantly improve the efficacy of ablation; simultaneous ablation can avoid the release of vascular endothelial factor caused by hypoxia after TACE and reduce the possibility of rapid tumor progression; because the patient is treated in the same hospitalization cycle, it can reduce the treatment cost of the patient. In summary, the combination of TACE Sequential ablation therapy is a safe and effective treatment. Another point of view is that TACE is used to treat tumors and then ablation therapy is performed, that is, the number or volume of tumors is reduced through TACE, and then tumor ablation therapy is further performed.

The current study [22] suggests that patients with liver cancer who meet the Milan criteria have a better prognosis after ablation than those who exceed the Milan criteria, and some patients who exceed the Milan criteria can be downgraded to within the Milan criteria through TACE, and can be obtained and early Similar long-term effects for liver cancer. Shi et al. [23] compared 72 liver cancer patients who received RFA treatment within Milan standards after downstage through TACE and 357 liver cancer patients who received RFA treatment within Milan standards, and compared the two groups of patients by propensity matching method1 The survival rates for, 3, and 5 years were 99% vs 94%, 80% vs 84%, and 66% vs 69%, respectively, and the recurrence-free survival rates were 73% vs 74%, 34% vs 43%, and 24% vs 37, respectively. %, there was no significant difference in survival rate and recurrence-free survival rate between the two groups. Shi et al. [24] further compared 66 patients with liver cancer who received MWA treatment within Milan standards after downstage through TACE and 190 patients with liver cancer who received MWA treatment within Milan standards. The survival rate and no recurrence of patients between the two groups were compared. There was also no significant difference in survival rates. The above results indicate that local ablation therapy after TACE treatment for large liver cancer can achieve the curative effect of early liver cancer patients after treatment.

3.2 Reduce residual tumor after ablation

Because of the irregular shape of large liver cancer, it is more difficult to completely inactivate during ablation treatment. Therefore, accurate preoperative imaging evaluation and planning are very important for the treatment of large liver cancer. Compared with conventional two-dimensional imaging images, three-dimensional tumor images are more suitable for clinicians to make preoperative planning, select appropriate needle insertion routes and formulate treatment plans. Especially for large liver cancer with a diameter greater than 5 cm, three-dimensional preoperative planning can significantly improve the complete ablation rate of the tumor and prolong the disease-free survival time of the patient.

Chinese scholar Liang Ping’s team [25] used 3D visualization software for ultrasound-guided MWA of large liver cancer, comparing the use and non-use of 3D visualization software to guide ablation treatment of large liver cancer patients, the results showed that the use of 3D visualization software to assist ablation treatment, the tumor is completely The ablation rate and the patient’s recurrence-free survival time are better than those of the control group. Schullian et al. [26] used three-dimensional visualization software to perform three-dimensional multi-needle RFA on large liver cancers with a diameter greater than 8 cm. A total of 41 primary liver cancer or metastatic lesions in 34 patients were included in the study. The average tumor diameter was 9.0 cm ( 8.0~18.0 cm), a total of 33 (80.5%, 33/41) tumors were completely ablated after one ablation treatment. The liver cancer patients included in this study (16 cases, 47.1%) survived for 1, 3, and 5 years The rates were 87.1%, 71.8% and 62.8%.

3.3 Reduce tumor recurrence rate after ablation

The 2007 SHARP study confirmed that the multi-kinase inhibitor sorafenib can benefit patients with unresectable advanced liver cancer, opening the preface of targeted therapy for liver cancer [27]. In recent years, researchers have initiated many clinical trials for the treatment of advanced liver cancer, and have made many breakthroughs. Currently, the commonly used targeted drugs for the treatment of advanced liver cancer in the clinic are sorafenib, regorafenib and rengel Vatinib et al. [28].

Although targeted drugs play an important role in the treatment of advanced liver cancer, their overall objective response rate is still Low, single-agent therapy has limited efficacy, and drug resistance is easy to occur [29], especially for patients with large liver cancer, and minimally invasive interventional therapy based on ablation therapy can significantly reduce tumor burden and reduce tumor targeting The drug resistance has played a synergistic treatment effect. The Chinese scholar Zhu Kangshun team [30] compared the use of RFA sequential TACE with and without sorafenib to treat patients with liver cancer of 3.0 to 7.0 cm.

The median survival time between the two groups was 63.0 months and 36.0 months, respectively (P= 0.048), the median progression-free survival time was 24.0 months and 10.0 months (P=0.04), the survival time and progression-free survival time of patients in the combination group were better than those in the non-combination group, and there was no significant difference in complications between the two groups . Zhu Kangshun and others believe that sorafenib can inhibit tumor neovascularization after TACE combined with RFA, and directly inhibit the proliferation of residual tumor cells, which has a significant synergistic effect of TACE combined with RFA treatment and reduces tumor recurrence after surgery.

4.  Future outlook

4.1 Immune combined ablation therapy

In recent years, with the emergence of immune checkpoint inhibitors such as PD-1/PD-L1 monoclonal antibody, immunotherapy has gradually changed the treatment of advanced tumors. However, previous clinical trials [31-32] showed that for patients with liver cancer, the objective response rate of immune checkpoint inhibitors such as PD-1 monoclonal antibody is low, and the survival benefit of patients is limited. In the IMbrave150 study [33], the use of atezolizumab combined with bevacizumab has made a major breakthrough in patients with unresectable liver cancer.

Compared with patients using sorafenib alone, it can improve the 1-year survival rate of patients (67.2 % vs 54.6%), and progression-free survival time (6.8 months vs 4.3 months). The IMbrave150 research has successfully opened up a new path for the immunotherapy of liver cancer, and the combined therapy of immunity and targeting will surely be an important way for the treatment of liver cancer in the future. Tumor immunotherapy includes the release of tumor antigens, antigen-presenting cells present antigens to T lymphocytes to induce an immune response, and finally specific T lymphocytes kill the tumor.

Among them, the release of tumor antigens is the most important starting link of immunotherapy, and liver cancer ablation therapy can promote the release of tumor antigens, activate T lymphocytes to kill tumors, and exert the patient’s own anti-tumor immune response. However, tumor tissues can achieve immune escape by up-regulating the expression of immunosuppressive molecules such as PD-L1, and reduce the efficacy of tumor ablation-induced immunotherapy [34].

The combined use of immune checkpoint inhibitors after ablation can effectively inhibit tumor immune escape and improve ablation. Induction of the efficacy of immunotherapy. Local ablation promotes antigen release and immune checkpoint inhibitors reduce immune escape. The combined use of the two will further significantly improve the efficacy of tumor immunotherapy and benefit more patients. How to combine the immune effects and immunity induced by ablation The combination of treatment remains to be further explored [35].

4.2 Hepatic artery infusion chemotherapy (HAIC) combined with ablation therapy

HAIC is to inject chemotherapeutic drugs directly into the blood vessel of the tumor through the hepatic artery through a microcatheter. While increasing the local chemotherapeutic drug concentration of the tumor, it significantly reduces the systemic side effects. Currently commonly used HAIC regimens in liver cancer are cisplatin-based FP regimen [36], and oxaliplatin-based FOLFOX chemotherapy regimen [37-38]. FOLFOX’s HAIC program is currently one of the important treatments for patients with unresectable liver cancer in China.

Chinese scholars Shi Ming et al. [39] carried out a prospective, randomized phase III clinical trial, which included a total of 247 cases of advanced liver cancer with portal vein tumor thrombi. Patients were randomly divided into HAIC plus sorafenib group and sorafenib group. The study showed that sorafenib combined with HAIC treatment significantly improved the median survival time of patients compared with sorafenib single agent (13.37 months vs 7.13) Months) and progression-free survival time (7.03 months vs 2.6 months). At present, many scholars are conducting clinical research on hepatic artery perfusion combined with targeted drugs and immune checkpoint inhibitors in the treatment of unresectable advanced liver cancer.

Early data has shown exciting effects. Previous studies [40] have shown that some patients with unresectable advanced liver cancer can get surgical resection again after HAIC treatment. However, when the tumor volume shrinks after comprehensive treatment and meets the indications for local ablation, can ablation treatment be similar to surgical resection? The curative effect still needs further research.

5 summary

Patients with large liver cancer are generally severely ill, often with severe liver cirrhosis, multiple intrahepatic lesions, or tumor vascular invasion. Only a small number of patients can tolerate surgery, and the prognosis of patients is poor. The rapid development of tumor ablation technology has brought new options for the treatment of patients with large liver cancer.

The treatment plan of TACE combined with local ablation can significantly improve the patient’s condition and prolong the survival time. In the process of ablation treatment, it is necessary to select the appropriate ablation treatment time according to the characteristics of each patient, make accurate preoperative planning, and combine targeted drugs and immune drugs as needed after the operation.

With the continuous advancement of various technologies, the treatment of large liver cancer is bound to enter a new era, and ablation will play an increasingly important role in the treatment of large liver cancer.

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