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 diagnosis and treatment of liver cancer; it has provided clear diagnosis for patients with suspicion; it has provided treatment opportunities for patients who are not suitable for open surgery; and it can even achieve radical 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 for diagnosis and treatment of liver cancer in recent years.
1.Laparoscopic techniques
1.1 Laparoscopic diagnosis of hepatocellular carcinoma is not 100% reliable even under the guidance of enhanced CT combined with AFP, and there is some ambiguity in preoperative imaging staging. de Santambrogio R et al [1] prospectively studied 104 patients with liver tumors and found lesions undetected by preoperative imaging in 26 patients (25%) using laparoscopic ultrasound technique. de Castro Sm et al [2] retrospectively analyzed 33 patients with primary hepatocellular carcinoma who first underwent laparoscopic exploration, which proved unresectable in 13 patients (39%), thus avoiding unnecessary open surgery. kim RD et al [3] prospectively studied 18 patients with progressive cirrhosis combined with hepatocellular carcinoma, and after laparoscopic exploration, 12 patients changed the stage determined on the basis of preoperative imaging, thus changing the treatment accordingly. thereby changing the treatment accordingly. For the diagnosis of laparoscopic hepatocellular carcinoma, it is currently accepted that: (1) it can detect tumors that are not detected by preoperative imaging and avoid omission or residual; (2) it can clarify the pathological nature of intrahepatic occupying lesions and avoid unnecessary liver resection; (3) it can clarify the stage of hepatocellular carcinoma and guide the choice of treatment.
1.2 Laparoscopic hepatectomy Arii S et al [4] retrospectively analyzed the results of a group of surgical resection (8010 cases in the hepatectomy group) and a group of non-surgical resection (4037 cases in the intratumoral anhydrous alcohol injection group and 841 cases in the hepatic artery embolization group) for the treatment of small hepatocellular carcinoma and showed that the hepatectomy group had higher survival rates. It can be seen that hepatectomy is the best choice to achieve the ideal treatment effect. However, open hepatectomy is very traumatic and requires high requirements on patients’ general condition, slow recovery and more complications after surgery, which makes its application greatly limited. Laparoscopic liver resection has compensated for these disadvantages by being minimally invasive, enabling the use of liver resection on a wider scale.
Gagner et al. first reported laparoscopic liver resection in 1992, and many successful treatments for liver tumors have been reported since then, including focal liver resection, segmental liver resection, and hepatic resection.
Rogula T et al [5] summarized the results of more than 700 laparoscopic hepatectomies, 70% of which were for benign tumors and 30% for hepatic malignancies, with a conversion rate of 11%, a complication rate of 12%, and a mortality rate of 0. Laparoscopic hepatectomy is considered feasible. Morino M et al [6] divided 60 patients into two groups (30 each) for paired analysis, and the mean tumor diameter (42 mm vs 41 mm), mean operative time (148 min vs 142 min), mean blood loss (320 ml vs 479 ml; P < 0.05), and postoperative complication rates in the laparoscopic group compared with the open group were 6.6%, no postoperative deaths, mean postoperative hospitalization days (6.4 days vs. 8.7 days; P < 0.05), and tumor margin < 1 cm (43% vs. 40%; P = NS). Laparoscopic liver resection was confirmed to be safe and feasible without adverse clinical consequences, and the patients benefited significantly. It can be concluded that, in the absence of significant differences in preoperative evaluation, laparoscopic surgery has a significant advantage over open hepatectomy in terms of blood loss, operative time, time to start bed activity, and length of hospital stay; while the differences in survival and tumor-free survival are not significant; demonstrating that laparoscopic surgery has a greater advantage in terms of patient quality of life [8].
For cases with huge cancer, laparoscopic surgery is also a more reliable option. Lang BH et al [7] reported 59 patients with ruptured hepatocellular carcinoma and bleeding, 33 cases were explored laparoscopically and 26 cases were explored openly. Thirteen cases in the laparoscopic group and eight cases in the open group had unresectable exploration results. There was no significant difference in the postoperative tumor-free survival and overall 3-year survival rate between the two groups who underwent liver resection, and the recurrence pattern was similar in both groups, with no disseminated metastasis from the surgical incision. It was confirmed that laparoscopic exploration could avoid unnecessary open surgery in patients with ruptured hepatocellular carcinoma with bleeding and had no adverse effects on tumor recurrence and postoperative survival.
For laparoscopic hepatectomy the current more consistent indications are: superficial hepatic occupying lesions in segments II-IV, especially marginal hepatic lesions located in the left outer lobe of the liver and the anterior segment of the right liver. With the development of laparoscopic technology and the accumulation of surgeons’ experience in using laparoscopy, reports of successful resection of right posterior lobe hepatocellular carcinoma have been published [9, 10].
2.Tumor local ablation therapy
In recent years, locoregional ablative procedure with minimally invasive features has been applied in the treatment of liver cancer, which is not only applicable to early and middle stage liver cancer and deep tumors, but also has good effect on advanced liver cancer. The basic principle is to use physical (such as radiofrequency ablation, microwave curing, laser, freezing) or chemical (such as intratumoral drug injection) methods to destroy tumor tissues to achieve the treatment purpose.
2.1 Radiofrequency ablation Radiofrequency ablation was firstly reported by Rossi in 1990 for the treatment of liver cancer, and it has received more and more attention at home and abroad. Its principle is to cause coagulation and necrosis of tumor tissues by generating ionic oscillation around the electrode needle through radiofrequency, resulting in hair potential. Usually, a spherical destruction area of about 3-3.5 cm in diameter can be formed each time, which is consistent with most tumor morphology. matsuno N et al [11] reported 19 patients with inoperable hepatocellular carcinoma due to severe cardiopulmonary disease or hepatic insufficiency, and after receiving radiofrequency ablation, 15 cases showed significant tumor necrosis with a 1-year survival rate of 84.2%. hsieh CB et al [12] reported 100 cases of decompensated stage cirrhosis combined with hepatocellular carcinoma were divided into laparoscopic radiofrequency ablation group (40 cases), hepatic artery chemotherapy group (20 cases), and conservative treatment group (40 cases), and the results showed that the complication rate was significantly lower in the radiofrequency ablation group and the survival rate was significantly higher.
Montorsi M et al [13] reported a prospective study of laparoscopic treatment of 98 patients with liver cancer combined with cirrhosis, divided into surgical group (40 cases) and radiofrequency ablation group (58 cases), the preoperative characteristics and postoperative recovery were similar in both groups, but the 4-year survival rate was lower and the intrahepatic recurrence rate was significantly higher in the radiofrequency ablation group compared with the surgical group. Teramoto K et al [14] reported 33 patients with liver cancer treated laparoscopically, divided into surgical group (15 patients) and radiofrequency ablation group (18 patients), and the 3-year survival rate was similar in both groups, but the 3-year tumor-free survival rate was lower in the radiofrequency ablation group. However, if radiofrequency ablation is performed before surgical resection, intraoperative bleeding can be effectively reduced [15].
With the development of RF ablation technology, its application in the treatment of hepatocellular carcinoma continues to be advanced, and there have been reports of successful application of the new arc probe in the treatment of hepatocellular carcinoma of the caudate lobe [16]. However, the correct and skilled use of RF ablation technique also depends on the experience of physicians [17]. To summarize the current indications: (1) tumors deep in the liver parenchyma, especially those with severe cirrhosis, radiofrequency only destroys the lesion while preserving as much normal liver tissue as possible; (2) tumor reduction of giant hepatocellular carcinoma; (3) radiofrequency ablation therapy can achieve the dual effect of hemostasis and tumor destruction if hepatocellular carcinoma ruptures and hemorrhage occurs; (4) it can be used as treatment before liver transplantation [18].
2.2 Microwave coagulation therapy The principle of microwave coagulation therapy for hepatocellular carcinoma is that the tumor tissue is exposed to microwave radiation and absorbs the microwave to produce high-speed oscillation, which is then converted into heat energy, causing the tumor tissue to coagulate and necrosis. The postoperative biopsy confirmed that 92.8% of the treated cancer nodules were tumor-free, and the cumulative survival rates from 1 to 5 years were 92.7%, 81.6%, 72.8%, 66.4%, and 56.7%, respectively. 63.9%. A more satisfactory treatment effect and survival rate were obtained. The indications are approximately the same as those for radiofrequency ablation.
2.3 Laser coagulation ablation In 1989, Steger et al. first applied laser photocoagulation (LP) to treat metastatic hepatocellular carcinoma successfully. The basic principle is that light energy is absorbed and converted into heat energy. The Nd:YAG laser with a wavelength of 1.64 mm has a low absorption rate, a high dispersion rate, the strongest penetrating power and a more uniform energy distribution. Heat conduction and conversion allow its cytotoxic effect to develop beyond 8 mm of light penetration into the surrounding tissue, thus causing cellular necrosis extending from the center outward. The necrotic zone expands with increasing energy, and if tumor necrosis is incomplete, heating can be repeated.Verhoef C et al [21] reported 24 patients with hepatocellular carcinoma, complete necrosis was observed in 79.2% (19/24) of cases after LP treatment, and there was no in situ recurrence at an average follow-up of 14 months after surgery.Ferrari FS et al [22] reported a randomized controlled study of 89 patients with liver cancer combined with cirrhosis patients, and concluded that laser treatment was more effective than other ablation methods when the tumor diameter was <50mm.
2.4 Cryoablation The main methods of cryoablation therapy are the traditional liquid nitrogen method and the newly emerged Ar-He cryoablation therapy in recent years. The basic principle is that when an ice ball is formed, its effect leads to cell dehydration, ion concentration and pH change, protein denaturation, cell membrane and other structural damage, while the combined effect of microvascular rupture causing hypoxia leads to cell death in the target area. The Ar-He knife is a thermally insulated hollow superconducting knife, which is cooled by high pressure argon gas at room temperature and rewarmed by high pressure helium gas at room temperature. The high pressure argon gas and helium gas pass through the knife head in sequence, forming a rapid freezing process followed by rapid warming (from -180°C to -20°C), and can be cycled several times in one operation. In addition, the patient’s body can produce a “low temperature effect”, which can mobilize the immune function and control the metastasis of liver cancer and produce immune effect on the metastatic cancer cells. The disadvantage of cryoablation is that the recurrence rate is higher than other ablation methods [23], and its indications are: (1) poor general condition that cannot tolerate surgical resection; (2) subfoci or tumor remnants at the cut edge after resection of the main tumor; (3) recurrent hepatocellular carcinoma that cannot be operated again; (4) metastatic multiple small hepatocellular carcinomas; (5) lesions near the bold duct or large blood vessels. The overall 1-year and 2-year survival rates were 76% and 61%, respectively, and the disease-free survival rates were 35% and 7%, respectively.
2.5 Drug ablation therapy Drug ablation therapy mainly uses intra-tumoral ethanol injection or acetic acid injection. It can be performed laparoscopically or by percutaneous puncture under ultrasound guidance. Ethanol and acetic acid are non-selective cellular protein denaturing agents that can dehydrate, coagulate and necrotize local hepatocellular carcinoma cells. Its diffusion to the peripheral blood vessels of the tumor can also destroy the endothelial cells of blood vessels and cause thrombosis, resulting in ischemic necrosis of cancer cells. Arii S et al [4] reported a multicenter prospective study in which 4,037 cases of small hepatocellular carcinoma were treated with intratumoral injection of ethanol, which achieved good efficacy, second only to that of hepatectomy. Single hepatocellular carcinoma smaller than 3 cm had better results with complete ablation rate of 80% and fewer complications; its results gradually became worse as the tumor increased in size and nodules [25].
The common features of the above methods are: local ablation of tumors by minimally invasive methods, which effectively kills tumor tissues while having less impact on the whole body and liver, and have the advantages of wide indications and less physical and economic burden on patients. These methods can not only be applied individually, but also combined with each other to improve the treatment effect and reduce the occurrence of complications. Xu KC et al [27] studied 65 patients and concluded that freezing combined with intratumoral drug injection could come close to achieving hepatic resection in some cases. In a randomized controlled study of 89 patients with hepatocellular carcinoma combined with cirrhosis, it was believed that the combination of multiple ablation methods could achieve complete necrosis of the lesion when the tumor diameter was >50mm.
3.Interventional treatment
At present, the effect of systemic chemotherapy for hepatocellular carcinoma is not satisfactory, and there is no single drug or combination chemotherapy regimen with an efficiency of more than 20%. Liver cancer requires >40Gy to achieve good local control, and the liver is very sensitive to radiation, and liver cancer patients are often combined with liver cirrhosis, and liver damage is very serious at this dose, which makes radiation therapy extremely limited. The emergence of interventional therapy has changed the insignificant status of radiotherapy and chemotherapy in the treatment of liver cancer. Currently, interventional therapy can be divided into two types of methods: interstitial intervention and vascular intervention.
3.1 Interstitial interventional chemotherapy and radiotherapy Local injection of chemotherapy drugs into the tumor can theoretically achieve higher therapeutic concentration than systemic chemotherapy. However, the drug can enter the circulation rapidly, so that it is difficult to achieve the expected purpose. With the introduction of slow-release agents in recent years, local injection of chemotherapeutic agents has become a new direction of intratumoral chemotherapy. Such extended-release agents consist of a bovine collagen gel encapsulating a stable and homogeneous cisplatin suspension and epinephrine. Pharmacokinetic studies have shown that the release of cisplatin into the circulation is delayed in cisplatin/epinephrine gels [28].Leung TW et al [29] studied 58 unresectable but more limited hepatocellular carcinomas by intratumoral injection of cisplatin/epinephrine gels and confirmed tumor necrosis in 53% of cases.Yu et al [30] reported 17 cases treated with this therapy and subsequently Gd (gadolinium) Enhanced T1 MR scans revealed no evidence of survival in 88% of the tumors.
Interstitial radiotherapy is the insertion of special, enclosed microscopic radioactive sources into the lesion in a certain order for irradiation. The basic principle has long been used in the post-mounted treatment of gynecologic and urologic tumors. According to the length of implantation time, it can be divided into: (1) permanent, that is, short half-life radionuclide sources such as 198Au, 192Ir, 137Cs, 125I permanently implanted in the tumor tissue without removal, in recent years, more use of 125I seed source; (2) non-permanent, that is, after the lesion tissue reaches a predetermined dose, the implanted radioactive source is then discharged. For example, the 192Ir seed source is strung with nylon thread into nodes and sutured for insertion.Ricke J et al [31] reported 37 patients with inoperable liver tumors, with a mean tumor diameter of 4.6 cm, adjacent to bold ducts or large blood vessels, with a control rate of 87% after 6 months of treatment with 192Ir insertion.
3.2 Vascular interventional chemo- and radiotherapy Hepatic artery chemoembolization (transarterial chemoembolization, TACE) is currently the treatment of choice for unresectable large hepatocellular carcinoma and multiple hepatocellular carcinoma. Hepatic artery embolization can cause ischemic necrosis of cancer foci, but because of the peripheral blood supply of portal vein, embolization alone can not achieve the goal of radical treatment. Hepatic artery embolization chemotherapy has a wide range of uses: it can be used as a preoperative measure to reduce tumor volume and create resection opportunities for large hepatocellular carcinoma; it can also be used as an adjuvant treatment after surgery; it can also be combined with other tumor ablation methods to improve the efficacy, and patients treated with multiple embolizations can achieve better results than those treated with one embolization [32, 33].
Intrahepatic radiotherapy embolization is based on the technique of chemoembolization and the injection of 90Y-microspheres, 131I-iodinated oil or isotope-labeled monoclonal antibodies, etc., which act as internal radiation therapy. necrosis. This method can cause abdominal irradiation if the microspheres leak into the abdominal cavity. However, the latest single-photon emission computed tomography (SPECT) technique can better guide 90Y-microsphere intratumoral injection and control the radioactive dose in different areas [35].
In conclusion, on the one hand, with the development of laparoscopic techniques, laparoscopic hepatectomy has been continuously applied and achieved exciting results, which greatly enriched hepatectomy for hepatocellular carcinoma. On the other hand, minimally invasive therapies such as local ablation of tumor and interventional radiotherapy and chemotherapy techniques have been more and more widely applied in the modern treatment of liver cancer and have achieved definite efficacy. They provide extremely important therapeutic tools for the comprehensive treatment mode of liver cancer. How to further expand the application scope of laparoscopic hepatectomy and improve its therapeutic effect; how to take advantage of the strengths and avoid the weaknesses in the application of minimally invasive treatments such as local ablation of tumor and interventional radiotherapy and chemotherapy techniques to better play its therapeutic role is the next direction of effort.