The history of interventional therapy for liver cancer in China

Abstract

In China interventional therapy of liver cancer started in the 1980s. It is well-known that Professor Lin Gui is the founding father of Interventional radiology. Under the leadership of Lin Gui and other professors, interventional therapy of liver cancer has swiftly progressed in China. Indeed, TAI, TAE, TACE and ablation therapy have witnessed great innovations in hardware facilities, technical means, and therapeutic philosophy, while incorporating Chinese characteristics. As with the development of combined interventional therapy in China, interventional treatment of liver cancer has gradually started the process of precision and individualization. Actually, multidisciplinary, multimodal, and polymorphic treatments will be the most suitable pattern for liver cancer in the future, among which combination of interventional therapy with targeted, immunological treatments and information technology (IT) tools may bring a revolutionary breakthrough in liver cancer treatment.

INTRODUCTION

Liver cancer is one of the most common malignancies in the world, with a high incidence of 780,000 new yearly cases. It is well-known that China is a country with a high burden of hepatitis. Meanwhile, the continuous rise of hepatitis incidence increases the hepatocellular carcinoma (HCC) burden, contributing to the fact that hepatocellular carcinoma patients in China account for about 50% of all cases worldwide. Therefore, liver cancer treatment has become the focus of medical investment in China (1). Most liver cancer patients show atypical progression, and are in advanced stage at diagnosis. Such cases can only receive non-surgical treatments, resulting in a surgical resection rate of only about 20% to 25%. Even in patients suitable for surgical resection, the 5-year recurrence rate is as high as 70% (2). Therefore, in recent decades, interventional therapy for liver cancer has emerged with the characteristics of minimal invasion, high efficiency, reduced side effects and good repeatability, and has gradually become an important treatment option in liver cancer. Although interventional therapy for liver cancer in China started relatively late, it quickly developed and now greatly influences the world. This article systematically reviews the development of interventional therapy for liver cancer in China.

In 1953 Seldinger invented arterial cannulation, and in 1964 Dotter reported the successful catheterization of the superficial femoral artery using coaxial catheterization, which represented the beginning of interventional radiology. However, it was in the 1970s that vascular intervention was introduced in China. In 1979, Lin Gui presented selective angiography for the diagnosis of hepatocellular carcinoma in China (3), and proposed that the interventional technique could also be used in the treatment of liver cancer. Then, Lin Gui carried out a series of animal and clinical studies on arterial embolization and published “Experimental liver and renal artery embolization and its clinical application” in 1981 in the Chinese Journal of Radiology (4), promoting interventional therapy for liver cancer in China. In 1985, Lin Gu proposed the dual blood supply theory of liver cancer (5-7), which laid the theoretical foundation for interventional therapy in liver cancer. In addition, Li Linsun in the 1980s multiple treatises and books on vascular intervention, attempting to promote the development of interventional therapy in China.

HEPATIC ARTERY INFUSION CHEMOTHERAPY (TAI)

TAI is the basic and one of the earliest techniques of interventional therapy in liver cancer. As early as the 1980s, TAI had become an important palliative treatment option for patients diagnosed with unresectable liver cancer (8). Its efficacy has been improved with the development of suitable regimens for arterial drugs and the understanding of their pharmacokinetics. For example, in 2017 hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin was applied in advanced hepatocellular carcinoma patients, and to some extent improved prognosis, with several patients even achieving complete remission (9). In additon (10), several guidelines have recommended TAI for colorectal liver metastases, establishing the irreplaceable usefulness of TAI in the treatment of liver metastases. Infusion pump implantation also made this therapeutic means more clinically convenient in China (11-13).

HEPATIC ARTERY EMBOLIZATION (TAE) AND HEPATIC ARTERIAL CHEMOEMBOLIZATION (TACE)

Compared with TAI, TAE and TACE are more widely applied in the field of liver cancer in China. In 1990 Luo Pengfei proposed scheduling hepatic arterial chemoembolization (LP-TAE) with the administration of chemotherapeutic drugs, e.g. lipiodol and gelatin sponge (14, 15), and initially confirmed that lipiodol-based hepatic arterial chemoembolization (cTACE) is effective and safe in small HCC and could prolong survival in massive HCC. Based on these findings, he emphasized the advantages of super-selective chemoembolization (16), and proposed a complete filling method for interventional treatment (17), in order to improve efficacy in liver cancer. Jia Yuchen assessed treatment outcomes in 468 patients with primary liver cancer receiving different interventional treatments in 1993, and found significantly improved curative effect in the lipiodol and gelatin sponge embolization group compared with the artery perfusion chemotherapy group, confirming the important status of cTACE in the treatment of liver cancer (18). In 1994, Han Guohong systematically evaluated hepatic segmental arterial chemoembolization, which yields better a curative effect and less side effects during cTACE. In addition, Han Guohong further explored the mode and outcome of lipiodol deposition after chemoembolization (19-21), and found that lipiodol selectively accumulates in areas rich in blood supply, providing a theoretical basis for evaluating cTACE efficacy. In 2006 Cheng Yongde systematically discussed the issues related to TACE treatment of refractory liver cancer, which contributed to solving the clinical problems of interventional therapy in liver cancer, and earned the Shanghai Medical Science and Technology Award (22). Xu ke applied the arsenious acid-lipiodol emulsion in the treatment of primary liver cancer in 2004 and showed a definite therapeutic effect, with less side effects; this is expected to further enhance the efficacy of cTACE (23, 24). In 2017, Zhao Ming proposed the concept of targeted-intratumoral-lactic-acidosis (TILA) TACE, which is expected to achieve stronger and more effective tumor cytotoxicity by changing the acidic tumor microenvironment based on cTACE. It is therefore obvious that lipiodol constitutes a traditional embolic agent with good functions of embolism and angiography but lacks good drug-carrying ability, and its deposition in tissues is not stable.

To overcome the insufficiency of lipiodol embolism and further improve TACE efficacy, new embolic agents have gradually emerged, including microspheres, drug-eluted microspheres, radioactive microspheres, and others. Chen Qinghua is one of the first doctors studying microsphere embolization in the treatment of liver cancer. In 1994, it was confirmed in animal models that hepatic artery embolization of microspheres significantly affects liver cancer (25), and microsphere embolization has gradually been introduced into clinic. Compared with lipiodol, microspheres are more stable and present a better carrier-effect, which might lead to improved therapeutic effects. In 2015, Zou Yinghua developed iodipin-loaded microspheres, which allows their detection by X-ray and CT, making clinical interventions safer and more convenient (26). On the other hand, drug-eluted microspheres have been rapidly developed in China. Stable embolization and drug pump function make drug-eluted microspheres more cytotoxic to tumors. A number of clinical studies have shown that drug-eluted microspheres exhibit better efficacy in the treatment of liver cancer (27, 28). Many Chinese professors have assessed new drug-loaded microspheres/particles, with great success. Bletilla granules, Curcuma aromatica oil microspheres, pingyangmycin-loaded ion exchange microspheres and doxorubicin-loaded sodium alginate microspheres show certain therapeutic effects in animal experiments and clinical application (29-31). In 1996, Feng Gansheng assessed arterial embolization of bletilla granules in liver cancer therapy, and obtained better embolic efficacy compared with gelatin sponge particles, with an average survival period 19.8 months (32). Further studies found that bletilla granules might cure liver cancer by inhibiting tumor angiogenesis (33). In addition, arterial embolization of radioactive microspheres is of great significance for the treatment of metastatic colorectal cancer in the liver, and significantly improved the benefits of systemic chemotherapy. Indeed, radioactive microspheres have been studied for a long time in China. In 1992, Yan Zhiping summarized the rationale and application of radioactive microspheres (34), and performed embolization of yttrium glass microspheres⁹⁰ in 18 patients diagnosed with liver cancer in 1994, obtaining good effects (35).

Based on the above findings, TACE treatment of liver cancer in China has been greatly developed and widely applied. The emergence of new materials, equipment and technologies, such as large digital plate DSA, microcatheter, guide wire, balloon microcatheter (36-38), makes precise TACE treatment of liver cancer possible. In recent years, driven by the development of biomaterials, many professors, e.g. Xu Ke, have developed nanoparticle drug delivery systems to selectively locate the tumor site and perform targeted therapy. Besides, such systems can also be combined with gene therapy to achieve greater effects (39).

ABLATION

In the 1980s, a group of doctors led by Luo Pengfei noticed that intratumoral injection of chemical agents, such as anhydrous ethanol and acetic acid, can achieve complete necrosis in small cell hepatocellular carcinoma; therefore, they gradually introduced chemical ablation in liver cancer. In the 1990s, physical ablation became a major tool for non-surgical treatment of liver cancer.

Chen Minhua introduced radiofrequency ablation for liver cancer in the late 1990s (40), and performed several studies to assess its efficacy and complications, also highlighting the significance of contrast-enhanced ultrasound in radiofrequency ablation of liver cancer. Meanwhile, Dong Baowei introduced the microwave tumor ablation technology in China and further improved it. Accordingly, Liang Ping further explored the value of ultrasound-guided microwave ablation in the treatment of liver cancer in 1997 (41). Compared with radiofrequency ablation, microwave ablation was shown to have higher efficiency and wider necrosis range, and was quickly developed. Lv Mingde and Xie Xiaoyan performed more in-depth studies of liver cancer ablation (42), and performed clinical trials from 2002 confirming that ultrasound-guided thermal ablation has good local therapeutic effects and improved three-year survival rate in early-stage liver cancer (43). In addition, although Chen Min-shan and Ma Kuan-sheng were hepatobiliary surgeons, they also attempted to promote thermal ablation therapy for liver cancer treatment in China. In 2005, Chen Min Shan carried out a randomized controlled study comparing surgery and percutaneous radiofrequency ablation. The final results showed that compared with surgical resection, percutaneous radiofrequency ablation has the same therapeutic effect in small cell hepatocellular carcinoma and even better short-term effects with tumor size ≤3 cm, thus laying an irreplaceable basis for thermal ablation in the treatment of liver cancer (44). Recently, Xu Xuemin combined cryoablation and radiofrequency ablation into a multi-modal ablation therapy system, allowing doctors to accurately control the range and effect of ablation; this is of great significance for liver cancer treatment. In 2014, Huang Jinhua used 30% hydrochloric acid infusion during radiofrequency ablation to efficiently expand the scope of ablation (45), for the treatment of large liver cell cancer and cancer originating from the caudate lobe.

As one of the physical ablation methods, cryoablation has its own advantages in the treatment of liver cancer. In 2005, Guo Zhi applied cryoablation in 26 cases of large cell hepatocellular carcinoma and obtained reduced tumor load in short term as well as increased quality of life (46-48). The latter authors suggested that cryoablation significantly improves the anti-tumor immune response in the human body and ameliorates liver function, promoting the development of cryoablation for liver cancer.

The HIFU ablation system invented independently by Chinese scientists could also be used for thermal ablation of tumors (49). Wang Zhibiao was one of the pioneer physicians using HIFU in China. Since the 1990s, has he explored the mechanism of HIFU, using it to treat liver cancer in 13 patients (50). Finally the latter study showed that treating liver cancer with HIFU was effective and feasible, indicating that applying this technology would provide a new non-invasive clinical treatment option for liver cancer, which could help strengthen the international influence of China in the field of interventional therapy for liver cancer.

In recent years irreversible electroporation technology (IRE) has gradually attracted interventional physicians. Actually compared with the radio frequency and microwave ablation methods, there is no heat sink effect during IRE. In addition, IRE would not cause injury to collagen rich tissues, including blood vessels, nerves and the bile duct, and is extremely suitable for ablation in dangerous sites (51). Because of these advantages, doctors like Zhang Xin, Ning Zhouyu and Lai Longxiang applied IRE in the treatment of advanced liver cancer, with accumulated clinical experience (52, 53).

Another non-vascular interventional therapeutic option for liver cancer also included brachytherapy, but had a short history in China and was not applied in clinical therapy until 1998 when the China Institute of Atomic Energy successfully developed radioactive I¹²⁵ and PD¹⁰³. In spite of this, with help from researchers such as Zhang Fujun, liver cancer treatment with radioactive particles has been gradually promoted (54). Radioactive seed implantation has better safety than ablation and can be used to treat specific liver cancers such as tumor around the portal vein as well as portal vein tumor thrombosis (55-57), improving patient prognosis.

With the development of digital information technology represented by computers and network technologies, interventional therapy of liver cancer in China would become digitized and intellectualized in future. Digital three-dimensional reconstruction can transform two-dimensional CT and MRI images into three-dimensional images, which allow preoperative visualization planning and may help achieve intraoperative real-time three-dimensional navigation. An intraoperative digital temperature control system can accurately monitor and adjust the ablation temperature, effectively enhancing treatment efficacy and ablation controllability. Indeed, medical big data is an important development direction in the future. Massive high-quality medical data on one hand can be used to guide and standardize operations in primary hospitals. On the other hand, data can be entered into artificial intelligence to construct robot operating systems for the interventional treatment of liver cancer; even full artificial intelligence diagnosis and treatment are expected to be feasible in the future.

INTERVENTIONAL COMBINATION THERAPY

Liver cancers in China mainly consist of large cell liver cancer, and are prone to local recurrence and metastasis. Although interventional means are increasingly available to physicians, a single interventional therapy is usually unable to meet the clinical demands, and two or even more combined interventional techniques and sequential therapy have gradually become a breakthrough in improving patient prognosis. In the late 19^th century, a dual interventional treatment strategy was proposed for large liver cell cancer, with repeated percutaneous transhepatic intratumoral injection of anhydrous ethanol and lipiodol after arterial chemoembolization (58). Clinical studies revealed that such strategy significantly alleviate necrosis in large cell liver cancer. In 2003 Wu Peihong confirmed the efficacy and advantages of TACE followed by radiofrequency ablation in the treatment of patients with advanced liver cancer, providing a basis for combined interventional therapy in liver cancer (59). Then, an increasing number of studies have shown that combined interventional therapy has obvious advantages over single interventional therapy, e.g. TACE combined with brachytherapy for liver cancer, TACE combined with endovascular ablation for portal vein tumor thrombus. It is apparent that interventional combination therapy has become an important component of liver cancer therapy. What’ more, many researchers further completed and innovated this strategy. Wang Jianhua combined I¹²⁵ radioactive particle scaffolds with TACE to treat liver cancer with portal vein tumor thrombus, with good short-term effects (60). To improve large cell liver cancer treatment, Huang Jinhua performed hepatic arterial embolization and multi-source microwave ablation simultaneously under guidance by a three-dimensional visualization system (61). In this way, the side effects of chemotherapeutic drugs could be avoided while increasing ablation efficiency, providing a viable treatment regimen for patients with large cell liver cancer.

Because of progress in technology and concept, interventional therapy for liver cancer has gradually stepped into the door of individualized therapy; compared with drug treatment limited by gene polymorphism and variability, interventional therapy has improved universality and stability.

MULTI-MODAL INDIVIDUALIZED TREATMENT

Although a diversity of techniques and methods in interventional therapy for hepatocellular carcinoma allow physicians to achieve individualized treatment to some extent, interventional therapy has obvious defects. First, interventional therapy cannot evaluate and address minimal residual disease. Currently, ablation therapy can only reach the evidence-based safety margin of the tumor, which is obviously not sufficiently “accurate”. Secondly, interventional therapy, after all, is only a partial or regional treatment, and not suitable for liver cancer patients with multiple metastases. Finally, some complications in patients could not be handled by interventional physicians. Therefore, multidisciplinary, multimodal, and polymorphic therapy will be the most suitable pattern for liver cancer in the future. Since early 21^st century, many professors have emphasized that interventional therapy should be organically combined with radiotherapy, systemic chemotherapy, surgical treatment, biological gene therapy, and traditional Chinese medicine to further improve patient prognosis in liver cancer (62). Professor Cheng Yongde explored the combination of interventional therapy and immunotherapy, using arterial perfusion of interleukin 2 (IL-2), lymphokine-activated killer cells (LAK), and tumor necrosis factor (TNF) to treat liver cancer for improved curative effects (63).

Targeted therapy is a powerful tool for interventional physicians in China. Sorafenib has been formally incorporated into treatment regimens for hepatocellular carcinoma by the China health and family planning commission. In 2011, a study confirmed that TACE combined with Sorafenib has good long-term effects in advanced liver cancer (64), with the two therapeutic modalities complementing and reinforcing each other from a mechanistic angle (65). In addition, a series of new targeted drugs, such as Regorafenib and Apatinib, could also be used in monotherapy or multimodality therapy of liver cancer.

In recent years, immunotherapy has attracted wide attention in the multimodality treatment of cancer. Indeed, as early as 2002, Chinese scientists reported the association of immunity with interventional therapy (66-68). Some even attempted to treat small cell hepatocellular carcinoma with radiofrequency ablation combined with arterial infusion of CIK cells (67), but beneficial responses from patients were not obtained. However, the development of immune checkpoint inhibitors (CTLA-4, PD-1/PD-L1) opened a new area for cancer immunotherapy. Currently, many medical centers in China focus on the local (interventional) + systemic (immunomodulatory) treatment model. Although evidence is not strong for now, it is obvious that this model is revolutionizing the treatment of liver cancer.

With years of dedication and hard work of many pioneers, interventional therapy for liver cancer can be attributed a glorious history, and excellent traditions and standards have been inherited. Currently, interventional therapy in China develops brightly and rapidly, but only caution and introspection could help solve the existent problems and achieve steady progress in the future. First, the clinical guidelines of interventional therapy and physicians in China still need to be unified, to ensure proper qualification of interventional physicians and the application of interventional therapy in primary hospitals. Meanwhile, interventional treatment of liver cancer should be promoted. Secondly, interventional treatment of liver cancer remains an immature technique, with reduced usefulness in many cases. Therefore, interventional therapy should be closely combined with targeted/immunological therapies as well as information technology, to promote diagnosis and treatment in liver cancer for a new milestone.