1. CryocareTM targeted cryoablation therapy (also known as argon helium knife)
Argon helium knife is a kind of ablation therapy technology with a wide range of indications. Since 1998, more than 100 hospitals in the United States and more than 80 units in China have been equipped with argon helium knife equipment. It can perform precise cryo-resection of many kinds of tumors, and has made breakthroughs in the treatment of liver cancer, lung cancer, pancreatic cancer, prostate cancer, renal tumors, breast cancer and other fields. Intraoperative freezing is applicable to almost all substantial tumors. Unlike other ablation methods such as radiofrequency, argon helium knife freezing can treat both small tumors and tumors of larger size (diameter greater than 5cm) and larger number; due to the heat-releasing effect of intravascular blood flow, freezing is not easy to cause damage to large blood vessels to the point that tumors near large blood vessels that cannot be surgically resected can also be treated. According to the statistics of the 14th World Congress of Cryotherapy in November 2007, the number of tumor cases treated with CryocareTM argon helium knife cryotherapy in China has reached 11,000, of which more than 10 units have completed more than 500 cases, and some hospitals have already reached 4,000 cases of more than 30 kinds of diseases, and China is the country that treats the largest number of liver and lung cancers in the world.
The choice of treatment technology for a specific case may vary due to the different characteristics of various targeted ablation techniques. Dr. Zhang Keqin [4] compared argon helium knife cryoablation with radiofrequency (RFA) and microwave (MCT) thermocoagulation for the treatment of rabbit VX2 hepatocellular carcinoma, and found that the three types of minimally invasive treatments could achieve the best results in ablating rabbit VX2 hepatocellular carcinoma, whether it was in the area and diameter of ablation target area, the rate of complete ablation of the tumor in the ablation target area, or the rate of residual tumor cells in the ablation target area, and the rate of complete necrosis of the tumor cells in the ablation target area. In terms of ablation target area and transverse diameter, complete ablation rate of tumor cells in the ablation target area, residual rate of tumor cells in the ablation target area, and complete necrosis of tumor cells in the ablation target area, argon helium knife cryopreservation was superior to RFA and MCT, whereas RFA and MCT were comparable. In addition, the "boiling effect" of RFA and MCT caused the spread of tumor planting, which is an insurmountable problem in clinical practice, and all these aspects suggest that the clinical efficacy of argon helium knife cryoablation in the treatment of rabbit VX2 hepatocellular carcinoma may be better than that of RFA and MCT.
Clinical treatment has confirmed that the local ablation of argon helium knife has the same efficacy as that of radiation, chemotherapy, biological therapy, interventional therapy and other integrated therapies, biotherapy, interventional therapy and other comprehensive treatments, the efficacy is better than single treatment, the survival rate of 1 to 2 years is significantly improved, and its long-term efficacy depends on the choice of comprehensive treatment measures. When the mass is ≥4cm, especially when it is larger than 6cm, the treatment effect is poor, and the tumor is prone to recurrence or even increase in size. Therefore, the application of comprehensive treatment measures before and after treatment combined with other therapeutic methods is especially important. For example, for the treatment of lung cancer: Ar-He knife combined with interventional chemotherapy, combined radiotherapy, combined with traditional Chinese medicine, compared with pure radiotherapy, chemotherapy, interventional embolization, the survival rate of 1 year and 2 years have been significantly improved, and the clinical efficacy has been relatively satisfactory, and the above results indicate that Ar-He knife will become the necessary technology in the clinical treatment of lung cancer. The above results indicate that argon helium knife will become a necessary technology for clinical treatment of lung cancer. For tumors near the mediastinum, it is difficult to completely ablate with Ar-He knife locally, so Ar-He knife treatment can also be combined with other local treatment methods, and the combination with radiotherapy can greatly reduce the radiation dose, and the combination of drug implantation and radioactive particle implantation can improve the therapeutic efficacy and reduce the implantation dose of the particles, and the effective combination with other local and systemic therapies can change the concept of the current comprehensive treatment and improve the long-term therapeutic effect. Long-term therapeutic effect. At present, the treatment of argon helium knife is in the ascendant in China, but there is a lack of prospective, multicenter, randomized controlled clinical trials to observe its long-term efficacy in the treatment of lung cancer.
The argon-helium targeted therapy technology collaborative group has carried out more work, such as writing the world's first standardized treatment book, including the size of the ablation target area of animal and human solid tumor lesions, and the imaging changes after freezing. It is suggested that other targeted ablation techniques can follow suit.
2. Radiofrequency ablation (RFA) and microwave ablation (MWA)
The MWA and RFA technologies both started in the early 1990s, and the LeVeen umbrella electrode was certified by the U.S. FDA in 1996, which greatly expanded the application scope of RFA. Compared with other thermal ablation techniques, RFA is by far the more widely used technique worldwide, and more than 500 review papers can be retrieved.MWA is mainly carried out in Japan and China, while most of the reports on RFA originate from Europe and the United States, and it can be assumed that the therapeutic efficacy of the MWA and RFA techniques is basically the same. Radiofrequency electrodes have developed from the initial unipolar to multipolar, as well as cold-circulation radiofrequency treatment system, the disadvantage of which is that the range of one-time destructive foci is limited, with a maximum destructive volume of 3.5cm in diameter, and it is easy to retain lesions for cancers with diameters of >3cm or more. American RITA has developed a series of radiofrequency needles for different sizes of tumors. Tumors below 3cm in diameter can choose the first generation of umbrella multi-polar needles or unipolar needles; tumors from 3cm to 5cm in diameter should choose the second generation of anchor multi-polar needles; tumors from 5cm to more than 7cm in diameter should choose the newest third generation of cluster electrode needles, and special syringe pumps are used, which make the heat transfer faster and more uniform, and shorten the treatment time significantly, and the effect of treating large tumors is improved. time is greatly shortened, the effect of treating large tumors is more accurate, and the patient is more relaxed.
Some scholars have raised the question of how to combine radiofrequency therapy with chemotherapy and local radiotherapy to improve the efficacy in the treatment of advanced non-small cell lung cancer. For advanced non-small cell lung cancer, especially peripheral lung cancer, radiofrequency ablation therapy is used first to inactivate cancer cells in the mass in a large area and reduce the tumor load, and then chemotherapy is used to treat the residual metastatic cancer cells. For patients with hilar and mediastinal lymph nodes or other metastatic lesions, radiotherapy and other treatments can be combined with chemotherapy. In this way, on the basis of local control of the tumor, the quality of patient survival and survival time are further improved. With the continuous improvement of RFA technology, the organic combination of RFA with interventional chemotherapy, stereotactic radiotherapy and external irradiation will greatly improve the local control rate of the tumor, improve the quality of life, and prolong the survival of patients.
3. Interstitial laser therapy (ILT) and photodynamic
ILT is a laser ablation therapy (ILT), in which a high-energy beam of optical or near-infrared wavelengths is scattered in the tissues and converted into heat, and the time is usually longer than that of RFA, and it can be more than 1 h. The ablation ranges of domestic and foreign laser tubes are small, and they are in clinical exploration, and have not entered the clinical field. that are in clinical exploration and have not entered clinical use. Pilot studies of composite probes are attempting to expand the ablation range.
4. High-intensity focused ultrasoundablation (HIFU)
HIFU is the first of its kind in China, and currently there are 4-5 manufacturers, each with a different frequency for the design of the probe. and malignant tumors, such as uterine fibroids, breast cancer, bone and soft tissue tumors. Clinical studies have been reported in China on the application of HIFU in the treatment of advanced pancreatic cancer, showing the efficacy of pain relief and changes in tumor volume after adjuvant radiotherapy and chemotherapy, which may be the effect of ultrasonic hyperthermia, and is not the true meaning of HIFU ablation therapy. Domestic literature shows that HLFU has an inactivating effect on a variety of solid tumors, including primary and metastatic hepatocellular carcinoma. However, there are still many limitations in the application of HIFU treatment for hepatocellular carcinoma, such as although part of the ultrasound waves can enter the liver tissue through the intercostal space, the rib reflection greatly reduces the energy of ultrasound waves to reach the target area; the long treatment time increases the risk of anesthesia session of HIFU treatment; the skin burns caused by HIFU treatment limit its therapeutic dosage; and the destruction of hepatocellular carcinoma tissues by HIFU treatment increases the chances of liver damage. Therefore, how to improve the biological effect of ultrasound and reduce the treatment time of HIFU has become one of the keys to the success or failure of this treatment.
5. Precision-targeted external radiation therapy technology
(1) x-knife, r-knife, 3D-CRT, IMRT
Radiation therapy technology has made a qualitative leap at the end of the 20th century, which is mainly embodied in stereotactic radiosurgery (SRS), stereotactic radiotherapy (SRT), three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated The clinical application of IMRT, SRS, SRT, 3D-CRT and IMRT technologies has fundamentally changed the role and status of radiotherapy, which has been in the auxiliary status of tumor treatment for nearly a century. During the introduction of Swedish head r-knife, European and American x-knife, and the clinical application of three-dimensional conformal radiotherapy technology, China has created a new situation of head and body r(x)-knife in Chinese mode. The clinical application of this technology has been more widely used, achieved better results, and received high attention from domestic and foreign colleagues.
x-knife in China in the late 1990s the application of the more popular, more treatment cases, but the lack of large cases of long-term clinical results reported after 2000 with the emergence of three-dimensional conformal radiotherapy, intensity-modulated radiotherapy and other technologies, in particular, China's whole-body r-knife, so that this technology in China's clinical application and development has been affected by the use of hospitals and the treatment of cases gradually decreased, but. It is indisputable that x-ray stereotactic radiotherapy technology, as a unique dose-focusing modality, can obtain highly concentrated dose distribution, and can achieve high local control rate and low radiation damage in the treatment of small tumors with parenchymal organ limitations. Moreover, the emergence of new x-knife technologies such as Cyberknife will play an important role in tumor treatment. The problems of the whole-body r-knife developed in China are that there are many models, insufficient development of hardware and software, and insufficient integration of resources, so that each model is not as good as it should be, especially in dose assessment and dose verification, which need to be further improved, and there is a serious lack of standardization of clinical application, which greatly affects the comprehensive and healthy development of this technology. Nevertheless, the unique dose-focusing advantage of whole-body r-knife has been proved by a large number of clinical results. Therefore, it is of great significance to strengthen the standardized clinical application of this technology, carry out multi-center collaboration and experience accumulation as well as further improve the equipment to promote the development of China's radiotherapy equipment industry and radiation oncology profession.
(2)Image-guided radiation therapy (IGRT) technology
IGRT, i.e., 4D radiation therapy, as well as bio-image-induced radiation therapy, which is under research and development, and so on. IGRT is developing rapidly in the developed countries, such as CyberKnife, Tomotherapy, and so on.
CyberKnife (CyberKnife) is a new type of image-guided precision radiation therapy for tumors, which was developed by John Adler of the Department of Brain Surgery at the University of Stanford Medical Center in the United States in cooperation with Accuray, and was put into use in 1994, and was first introduced by Prof. Adler in 1997 for its clinical application. It is a stereotactic treatment machine that integrates an image guidance system, a highly accurate robotic tracking and targeting system, and a ray release irradiation system to accomplish the treatment of lesions at any site. A lightweight linear electron gas pedal capable of generating 6MV-X-rays is placed on a robotic arm with six degrees of freedom, and the low-dose three-dimensional images obtained from an operational X-ray camera and X-ray image processing system are used to track the location of the target area, execute the treatment plan, and "excise" the tumor with an accurate dose of radiation. It is considered to be one of the most accurate stereotactic radiosurgery/therapy (SRS/SRT) techniques in the world because its total clinical treatment accuracy can reach the sub-millimeter level. Compared with the traditional SRS/SRT technology, CyberKnife has the advantages of real-time image guidance and frameless localization. Since 1999 and 2001, when it was approved by FDA for the treatment of intracranial tumors, extracranial tumors and benign tumors, it has been 8 years of clinical application history, and more than 40,000 patients have received CyberKnife treatment all over the world. Especially in the treatment of intracranial tumors and spinal tumors, CyberKnife has accumulated rich experience, but in the treatment of body tumors, such as lung cancer, hepatocellular carcinoma, and tumors of the abdomen, it still remains in the small sample, short-term and short-term treatment. However, in the treatment of body tumors such as lung cancer, liver cancer, and abdominal tumors, CyberKnife is still in the stage of small-sample, short-term follow-up research. With the gradual promotion of the clinical application of Cyberknife in China and the increase in the number of clinical treatments and cases, especially in the treatment of complex and severe patients, the complications of implantation of gold standard in the tumor target area before Cyberknife treatment for solid malignant tumors in the body need to be further summarized, so that Cyberknife can be further standardized and rationally applied in China, and more patients with tumors can be benefited from it. Cyberknife has certain advantages over conformal, intensity-modulated, and gamma knife, and also provides the possibility of fractionated high-dose radiotherapy. How to choose the best segmentation mode and single dose, total dose, and how to evaluate the effective biological dose have become the urgent problems to be solved in the research. Under the existing conditions, combining the knowledge of radiobiology and clinical medicine, optimizing the treatment strategy, and carrying out the integrated treatment including sensitization of radiotherapy, chemotherapy, hyperthermia, and even other radiotherapy modalities, in order to improve the therapeutic efficacy as much as possible, will be the main direction of research in the future.
Helical tomotherapy, invented by the University of Wisconsin-Madison, is an image-mediated three-dimensional intensity-modulated radiation therapy, which integrates the linear gas pedal and helix to integrate the treatment plan, the patient's position, and the treatment process into a single entity, which is capable of treating different target areas, from stereotactic treatment of small tumors to systemic treatment, which are completed by a single helical beam. It is capable of treating different target areas, from stereotactic treatment of small tumors to systemic treatment, all of which are completed by a single spiral beam. Through the megavoltage images obtained from each treatment, the dose distribution of the tumor and the changes of the tumor during the treatment process can be observed, so that the treatment plan of the target volume can be adjusted timely. It has the incomparable advantages of conventional gas pedal radiotherapy, which opens up a new treatment platform for radiotherapists and occupies an important position in the development history of intensity-modulated radiation therapy.
7. Implantation of radioactive particles in interstitial irradiation therapy
The radioactive particles used in clinical application are mainly 125I and 103Pd, which represent low-dose-rate and medium-dose-rate radiation, and have their own characteristics in radiophysics and radiobiology, respectively. The process of implantation of radioactive particles should be accomplished under the guidance of imaging, in accordance with the requirements of IGRT, and the radioactive particles should be implanted in a single dose to achieve the effect of single-dose treatment.
With the continuous improvement and perfection of the particle implantation treatment planning system, the dosimetric requirements are gradually clarified, the implantation treatment equipment is constantly improved, and the clinical application of radioactive particles has been broadened in the past 20 years, which fully explains the role and status of the radioactive particles in the clinical application, and the radiotherapists from the United States, Germany, and Japan have recognized that the best indications for radioactive particles should be the cases in the low-risk group of prostate cancer. The long-term efficacy of radioactive particle therapy is similar to that of radical surgery or external irradiation, but the side effects, especially the incidence of sexual dysfunction, are lower, the treatment time is short, and the surgical method is simpler and more popular among patients. In expanding the indications of radioactive particle therapy, radiation oncologists and surgical experts firstly use radioactive particles to treat non-small cell lung cancer, and our thoracic surgeons have already achieved quite satisfactory results in the treatment of non-small cell lung cancer, and radioactive particle implantation has been used in the treatment of hepatocellular carcinoma (primary hepatocellular carcinoma and metastatic hepatocellular carcinoma), pancreatic carcinoma, soft tissue sarcoma, bone tumors, and early-stage breast cancer, etc. in the clinical trials. The treatment of liver cancer (primary liver cancer and metastatic liver cancer), pancreatic cancer, soft tissue sarcoma, bone tumor, early stage breast cancer, etc. have gained certain experience and efficacy in clinical trials. The trials of particle implantation in cavity tumors through endoscopy at home and abroad, and the trials of implantation of stent-carrying or bundled radioactive particles into luminal tumors (esophagus and bronchus) at home are all in the process of exploration and development.
The equipment for radioactive particles has been standardized, the most important of which is the treatment planning system (TPS), which must be able to meet the requirements of quality verification. Radioactive particle implantation brachytherapy has been rapidly developed in China, according to incomplete statistics, the country's monthly sales of 125I particles 20,000 to 30,000 particles, treatment of 4,000 to 6,000 cases of patients. Such a large-scale use of radiation therapy, there must be rules and regulations to guide the management of this work should be imminent, in addition, there should be a serious exchange of clinical experience with radioactive particles, so that the clinical use of radioactive particles is not only standardized, but also continue to improve the efficacy of treatment and reduce the toxicity of side effects.
8. Intravascular intervention and local drug injection
Vascular intervention of malignant tumors is to inject antitumor drugs and/or embolic agents into tumor nutrient arteries through catheters under the supervision of X-ray equipment to treat tumor lesions. Due to the development of catheterization instruments and imaging equipment, the continuous updating and increase in the variety of contrast agents, especially with the increase in the application of microcatheters, the accumulation of experience in the application of embolic agents, and the continuous improvement of interventional technology, the targeted intrathecal cannulae in the super-selective tumor supplying arteries for perfusion chemotherapy and embolization have become the routine work in the clinic. At the same time, the technology is less traumatic and easy to operate, and thus has been rapidly developed, improving the efficiency of this treatment method and prolonging the survival period of tumor patients. Local drug injection techniques, such as percutaneous alcohol injection for small hepatocellular carcinoma, percutaneous hepatic puncture injection of iodinated oil plus chemotherapeutic drugs for the treatment of liver tumors, and anhydrous alcohol, acetic acid, and hot saline injections for recurrent or residual lesions are routinely carried out in the clinic, with inexpensive cost and remarkable effect.
Transcatheter or percutaneous puncture intratumoral injection of gene therapy has become a hotspot of tumor research, and some studies have already entered the animal experiment stage, for example, endothelial inhibitory gene therapy for hepatocellular carcinoma given through the hepatic artery; adenovirus-mediated anti-K-ras ribosomal kinase can inhibit the growth of pancreatic cancer cells and induce their apoptosis; HSV-TK (herpes simplex virus thymine ribonucleoside kinase) mediated gene therapy in animal models have been used in the treatment of liver tumors. HSV-TK (herpes simplex virus thymidine nucleoside kinase)-mediated gene therapy has been initially successful in animal models; drug-sensitive genes, apoptosis-regulating genes such as bcl-2, bax, survivin, and some genes inhibiting angiogenesis in tumors are under extensive research. Recombinant human p53 adenovirus gene drug has been used in clinical practice by percutaneous intratumor injection. Due to the limitation of gene therapy for tumor treatment, so far only liver cancer, pancreatic cancer, lung cancer, glioma, colorectal cancer, laryngeal cancer and other tumors can be treated with interventional-directed gene therapy, but interventional-directed gene therapy has shown good efficacy in the treatment of certain tumors, reduced adverse reactions, and brought great benefits to the people, and it can be believed that, with the deepening of the research, interventional-directed gene therapy will play a greater role in the treatment of tumors. It can be believed that, with the deepening of research, intervention-oriented gene therapy will play a greater role in tumor treatment, and more and more tumors will be eradicated.
9. Nerve-targeted repair therapy
Nerve-targeted repair therapy makes nerve growth factor act on the damaged area through intervention. It activates dormant nerve cells, realizes self-differentiation and renewal of nerve cells, and replaces damaged and dead nerve cells, rebuilds the nerve circuits, increases the oxygen supply and blood circulation in the brain, and promotes the re-development of organs.
10, photodynamic therapy
Photodynamic targeted therapy refers to the participation of photosensitizers, under the action of light, so that the organism's cells or biomolecules undergo functional or morphological changes, leading to cell damage and necrosis in severe cases, and this effect must have the participation of oxygen, the photodynamic effect of the treatment of the disease is also known as the photodynamic therapy (photodynamic therapy). Photodynamic therapy (PDT). The research of targeted drugs, i.e. photosensitizers (photodynamic therapy drugs), is the key to the prospects of photodynamic therapy. Photosensitizers are special chemical substances whose basic role is to transfer energy, which can absorb photons and be excited, and then quickly transfer the absorbed light energy to another group of molecules, so that they are excited and the photosensitizer itself back to the base state.
Targeted therapy in the application of disease: warts, acne, bright red nevus, tumors, etc.
Therapy advantages:
(1) trauma is very small: with the help of fiber optics, endoscopy and other interventional techniques, the laser can be guided to the deep inside the body for treatment, avoiding the trauma and pain of the surgery, such as the opening of the chest, open abdominal and so on.
(2) Low toxicity: The photosensitive drug that enters the tissue will trigger a photodynamic reaction and kill the targeted cells only when it reaches a certain concentration and is irradiated by a sufficient amount of light, which is a localized treatment method. The part of the human body that is not irradiated by light does not produce such a reaction, and the organs and tissues in other parts of the body are not damaged, nor does it affect hematopoietic function, so the toxicity and side effects of photodynamic therapy are very low.
(3) Good selectivity: the main target of attack is the diseased tissue in the light-illuminated area, and the damage to the normal tissues around the lesion is slight, and this selective killing effect is difficult to be realized by many other therapeutic means.
(4) good applicability: the different cell types of the lesion tissue are effective, wide range of application; and different cell types of the lesion tissue on radiotherapy, chemotherapy sensitivity can have a greater difference, the application is limited.