What Is Targeted Therapy?

1. Argon-helium superconducting surgical treatment system (cryocareTM targeted cryoablation therapy, also known as argon-helium knife)
Argon-helium knife is an ablation therapy technique 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, which can accurately freeze a variety of tumors. Resection, and has made breakthroughs in the treatment of liver cancer, lung cancer, pancreatic cancer, prostate cancer, kidney tumor, breast cancer and other fields. Intraoperative cryotherapy is suitable for almost all solid tumors. Unlike other ablation methods such as radiofrequency, argon-helium knife cryotherapy can treat small tumors as well as larger tumors (>5cm in diameter) and a large number of tumors; due to the vascular Due to the heat release effect of internal blood flow, freezing is not easy to cause damage to large blood vessels, so that it can also treat tumors near large blood vessels that cannot be surgically removed. According to the statistics of the 14th World Conference on Cryotherapy in November 2007, the number of tumor cases in China using CryocareTM argon-helium knife cryosurgery has reached 11,000 cases, of which more than 10 units have completed more than 500 cases, and some hospitals have reached 4,000 cases. , more than 30 kinds of diseases, China is the country with the most treatment of liver cancer and lung cancer in the world.
Due to the different characteristics of various targeted ablation techniques, the choice of treatment technique for specific cases may vary. A comparative study of cryoablation with argon-helium knife and radiofrequency (RFA) and microwave (MCT) thermal coagulation in the treatment of VX2 liver cancer in rabbits. The three minimally invasive treatments were used in ablation of VX2 liver cancer in rabbits. In terms of the complete tumor ablation rate in the target area, the residual rate of tumor cells in the ablation target area and the complete necrosis rate of tumor cells in the ablation target area, argon-helium knife freezing is superior to RFA and MCT, while the effects of RFA and MCT are comparable. In addition, tumor seeding and dissemination caused by the “boiling effect” of RFA and MCT is an insurmountable clinical problem. All these aspects suggest that the clinical efficacy of argon-helium knife cryotherapy in the treatment of VX2 liver cancer in rabbits may be better than that of RFA and MCT.
Clinical treatment has confirmed that the combination of argon-helium knife local ablation and comprehensive treatments such as radiotherapy, chemotherapy, biological therapy, and interventional therapy is superior to single therapy, and the 1-2-year survival rate is significantly improved. choose. When the mass is larger than 4 cm, especially larger than 6 cm, the treatment effect is poor, and the tumor is prone to recurrence or even enlargement. Therefore, the application of comprehensive treatment measures combined with other treatment methods before and after treatment is particularly important. For example, for the treatment of lung cancer: argon-helium knife combined with interventional chemotherapy, combined with radiotherapy, combined with traditional Chinese medicine treatment, compared with radiotherapy, chemotherapy, and interventional embolization alone, 1 year The 2-year survival rate was significantly improved, and a satisfactory clinical effect was obtained. The above results show that the argon-helium knife will become an essential technology for the clinical treatment of lung cancer. For tumors close to the mediastinum, it is difficult to completely ablate the local argon-helium knife. After the argon-helium knife treatment, other local treatment methods can also be combined. Combined with radiotherapy, the radiation dose can be greatly reduced, and the combination of drug implantation and radioactive seed implantation can Improving the efficacy and reducing the dose of implanted particles, combined with other local treatment and systemic treatment techniques, can change the current concept of comprehensive treatment and improve the long-term treatment effect. At present, the treatment of argon-helium knife is in the ascendant, but there is a lack of prospective, multi-center, randomized controlled clinical trials to observe its long-term efficacy in the treatment of lung cancer.
The Argon-Helium Targeted Therapy Technology Collaboration Group has carried out a lot of work, such as the compilation of the world’s first standardized treatment book, including the size of the ablation target volume 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)
Both MWA and RFA technologies started in the early 1990s. In 1996, the LeVeen umbrella-shaped multi-electrode was certified by the US FDA, which greatly expanded the application scope of RFA. Compared with other thermal ablation technologies, RFA is the most widely used in the world so far. More than 500 review literatures can be retrieved. MWA is mainly carried out in Japan and my country, and most of the reports on RFA come from European and American countries. It can be considered that the therapeutic effect of MWA and RFA technology is basically the same. The radiofrequency electrode has developed from the original monopolar to multipolar, and the cold cycle radiofrequency treatment system. The disadvantage is that the scope of the one-time damage is limited, and the maximum damage volume is 3.5cm in diameter. RITA Corporation of the United States has developed a series of radiofrequency needles for tumors of different sizes. For tumors with a diameter of less than 3cm, the first-generation umbrella-shaped multipolar needle or monopolar needle can be selected; for tumors with a diameter of 3cm to 5cm, the second-generation anchor-shaped multipolar needle should be selected. ; For tumors with a diameter of 5cm to 7cm or more, the latest third-generation cluster electrode needle should be selected, and a special syringe pump should be used to make the heat conduction faster and more uniform, the treatment time is greatly shortened, the treatment effect of 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 curative effect in the treatment of advanced non-small cell lung cancer. For advanced non-small cell lung cancer, especially peripheral lung cancer, radiofrequency ablation is used first to inactivate the cancer cells in the mass in a large area to reduce the tumor load, and then chemotherapy is used to treat the residual metastatic cancer cells. For patients with hilar, mediastinal lymph nodes or other metastatic lesions, radiotherapy and other treatments can be combined with chemotherapy. In this way, the quality of life and the survival time of patients are further improved on the basis of local control of the tumor. 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 tumors, improve the quality of life, and prolong the survival period of patients.

3. Interstitial laser therapy (ILT) and photodynamic
Laser ablation therapy (ILT) converts high-energy beams of optical or near-infrared wavelengths into heat by scattering in tissue, usually longer than RFA, and can exceed 1 hour. The laser tube produced has a small ablation range and is in clinical exploration and has not been used clinically. Trials have investigated compound probes in an attempt to expand the scope of ablation.

4. High-intensity focused ultrasound (HIFU)
There are currently 4-5 HIFU manufacturers, and the design of the probe has different frequencies. HIFU can be used for the treatment of many benign and malignant tumors, such as uterine fibroids, breast cancer, bone and soft tissue tumors. There are successive reports of clinical studies on the application of HIFU in the treatment of advanced pancreatic cancer in the market. The curative effects shown are mainly pain relief and changes in tumor volume after adjuvant radiotherapy and chemotherapy. This may be the effect of ultrasonic hyperthermia, not HIFU ablation therapy in the true sense. Literature has shown that HLFU can inactivate a variety of solid tumors, including primary and metastatic liver cancer. However, there are still many limitations in the application of HIFU in the treatment of liver cancer. For example, although part of the ultrasound can enter the liver tissue through the intercostal space, the rib reflection greatly reduces the energy of the ultrasound reaching the target area; too long treatment time increases the risk of anesthesia in HIFU treatment. ; Skin burns caused by HIFU treatment limit the increase of its therapeutic dose; HIFU treatment increases the chance of liver damage while destroying liver cancer tissue. 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 the treatment.

5. Precision Targeted External Radiation Therapy
(1) x-knife, r-knife, 3D-CRT, IMRT
Radiation therapy technology made a qualitative leap at the end of the 20th century, mainly reflected in stereotactic radiosurgery (SRS), stereotactic radiotherapy (SRT), three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) techniques The clinical application of radiotherapy has fundamentally changed the role and status of radiotherapy, which has been in the adjuvant position of tumor treatment for nearly a century. In the process of introducing the 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 the head and body r(x)-knife of the Chinese model. The clinical application of this technology is relatively extensive, and good results have been achieved, which has attracted great attention.
In the late 1990s, the x-knife was widely used in my country, and there were many cases of treatment, but there was a lack of long-term clinical results reported in a large number of cases. – The advent of knives has affected the clinical application and development of this technology in my country, and the number of hospitals and treated cases has gradually decreased. However, there is no doubt that x-ray stereotactic radiotherapy technology, as a unique dose-focusing method, can A highly concentrated dose distribution can be obtained, and a higher local control rate and lower radiation damage can be achieved in the treatment of small tumors confined to solid organs. 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 my country are that there are many models, insufficient software and hardware development and resource integration, so that each model is not perfect, especially in terms of dose evaluation and dose verification. There are serious deficiencies in the 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 necessary to strengthen this technology. Standardized clinical application of technology, multi-center collaboration and experience accumulation, and further improvement of equipment are of great significance to promoting the development of my country’s radiotherapy equipment industry and radiation oncology profession.

(2) Image-guided radiation therapy (IGRT) technology
IGRT is 4D radiation therapy, and bioimage induced radiation therapy is being developed, and so on. IGRT is developing rapidly in developed countries, such as CyberKnife, Tomotherapy, etc.
CyberKnife (CyberKnife) is a new type of image-guided tumor precision radiation therapy technology. its clinical application. It is a stereotaxic treatment machine that integrates an image guidance system, a high-accuracy robot tracking and aiming system and a ray release irradiation system, which can complete the treatment of any part of the lesion. A light-weight linear electron accelerator capable of generating 6MV-X-rays is placed on a robotic arm with 6 degrees of freedom, and the position of the target area is tracked by calculating the low-dose 3D images obtained by the X-ray camera and the X-ray image processing system. A treatment plan that “removes” the tumor with the exact dose of radiation. It is considered to be one of the most precise stereotactic radiosurgery/therapy (SRS/SRT) techniques in the world due to its total clinical treatment accuracy up to sub-millimeter level. Compared with traditional SRS/SRT technology, CyberKnife has the advantages of real-time image guidance and frameless positioning. Since it was approved by the US FDA in 1999 and 2001 for the treatment of intracranial tumors, extracranial tumors and benign tumors, it has been clinically used for 8 years. More than 40,000 patients around the world have received CyberKnife treatment, especially Cyberknife has accumulated rich experience in the treatment of intracranial tumors and spinal tumors, but the treatment of body tumors such as lung cancer, liver cancer, and abdominal tumors is still in the research stage of small samples and short-term follow-up. With the gradual promotion of the clinical application of Cyberknife in my country and the increase in the number of clinically treated diseases and cases, especially the development of the treatment of complex and severe patients, patients with solid malignant tumors of the body are treated with gold standard implantation in the tumor target area before Cyberknife treatment. Complications of the surgery need to be further summarized, so that the Cyber ​​Knife can be further standardized and reasonably applied in my country, and more tumor patients can benefit from it. Cyber ​​Knife has certain advantages over conformal, IM, Gamma Knife, etc. It also provides the possibility of fractional high-dose radiotherapy. How to choose the best fractionation method, single dose, total dose, and how to evaluate effective biological Dosage has become an urgent problem to be solved in research. Under the existing conditions, combined with the relevant knowledge of radiobiology, clinical medicine, etc., optimize the treatment strategy, carry out comprehensive treatment including radiotherapy sensitization, chemotherapy, hyperthermia and even other radiotherapy methods, and improve the efficacy as much as possible. It is the main research direction in the future.
Helical tomotherapy (Tomotherapy), invented by the University of Wisconsin-Madison, is an image-mediated three-dimensional intensity-modulated radiation therapy that integrates linear accelerators and spirals to make treatment planning, patient placement and treatment process

Integrating into one, it can treat different target areas, from stereotactic treatment of small tumors to systemic treatment, all completed by a single helical ray beam. Through the megavolt images obtained from each treatment, the tumor dose distribution and the distribution of tumor doses can be observed. Changes in the tumor during the treatment process, timely adjustment of the target volume of the treatment plan. It has the incomparable advantages of conventional accelerator radiotherapy, which has opened up a new treatment platform for radiotherapy physicians, and occupies an important position in the development history of intensity-modulated radiotherapy.

7. Radioactive Seed Implantation for Interstitial Irradiation Therapy
The main radioactive particles in clinical application are 125I and 103Pd, which represent low dose rate and medium dose rate radiation, respectively, and have their own characteristics in radiophysics and radiobiology. The process of implanting radioactive seeds needs to be completed under the guidance of imaging, which meets the requirements of IGRT, and the radioactive seeds are implanted at one time to achieve the effect of single dose treatment.
With the continuous improvement and improvement of the seed implantation treatment planning system, the gradual clarification of dosimetry requirements, and the continuous improvement of implanted treatment equipment, the clinical application of radioactive particles in the past 20 years has continued to expand the field, which fully demonstrates the role and status of radioactive particles in clinical applications. , German and Japanese radiotherapy experts all admit that the best indication of radioactive seeds should be the cases of low-risk group of prostate cancer. Its long-term efficacy is similar to radical surgery or external irradiation, but the incidence of side effects, especially sexual dysfunction, is lower. The treatment time is short, and the surgical method is simple and more popular with patients. In terms of expanding the indications of radioactive seed therapy, radiation oncologists and surgical experts first used radioactive seeds to treat non-small cell lung cancer. Experts in thoracic surgery in my country have achieved quite satisfactory results in the treatment of non-small cell lung cancer. Radioactive seed implantation is used to treat liver cancer. (Primary liver cancer and metastatic liver cancer), pancreatic cancer, soft tissue sarcoma, bone tumor, early breast cancer, etc. have obtained certain experience and efficacy in clinical trials. The experiment of implanting seeds into cavity tumors by endoscope, and implanting the radioactive seeds into the cavity tumors (esophagus, bronchus) by stents, are all in the process of exploration.
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 seed implantation brachytherapy has developed rapidly. According to incomplete statistics, 20,000 to 30,000 125I seeds are sold nationwide every month, and 4,000 to 6,000 patients are treated. Such a large-scale use of radiotherapy must be managed under the guidance of rules and regulations. This work should be imminent. In addition, the clinical experience of radioactive particles should be carefully exchanged, so that the clinical use of radioactive particles can not only be standardized, but also continuously improve the efficacy. Reduce toxic side effects.

8. Endovascular interventional therapy and local drug injection therapy
Vascular interventional therapy for malignant tumors is to inject antitumor drugs and/or embolizing agents into tumor nutrient arteries through catheters under the monitoring of X-ray equipment to treat tumor lesions. Due to the development of catheter equipment and imaging equipment, the continuous update and variety of contrast agents, especially with the increase in the application of microcatheters, the accumulation of experience in the application of embolic agents, the continuous improvement of interventional technology, and the targeted cannulation in super-selective tumor blood supply arteries Infusion chemotherapy and embolization have become routine clinical work. At the same time, the technology is less invasive and easy to operate, so it has been rapidly developed, which improves the efficiency of this treatment method and prolongs the survival period of tumor patients. Local drug injection treatment techniques, such as percutaneous alcohol injection for small liver cancer, percutaneous liver puncture and injection of lipiodol plus chemotherapy drugs for liver tumors, and injection of absolute alcohol, acetic acid, and hot saline for recurrent or residual lesions are all routinely carried out in clinical practice. Inexpensive and effective.
Transcatheter or percutaneous intratumoral injection of gene therapy has become a hot spot in tumor research, and some studies have entered the stage of animal experiments, for example, endostatin gene therapy through hepatic artery; adenovirus-mediated anti-K-ras ribosomal kinase It can inhibit the growth of pancreatic cancer cells and induce their apoptosis; HSV-TK (herpes simplex virus thymidine 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 that inhibit angiogenesis in tumors are all under extensive research. The intratumoral injection of recombinant human p53 adenovirus gene drug has entered clinical use. Due to the limitations of gene therapy for tumors, so far only a few tumors such as liver cancer, pancreatic cancer, lung cancer, glioma, colorectal cancer, and laryngeal cancer can use intervention-oriented gene therapy. It has shown a good curative effect in the treatment of cancer, reduced adverse reactions, and brought great benefits to people. It is believed that with the deepening of research, intervention-oriented gene therapy will play a greater role in tumor treatment. More and more tumors will be cured.

9. Nerve-targeted repair therapy
Nerve-targeted repair therapy allows nerve growth factor to act on the injury site by interventional means. It activates dormant nerve cells, realizes self-differentiation and renewal of nerve cells, replaces damaged and dead nerve cells, rebuilds neural circuits, increases oxygen supply and blood circulation to the brain, and promotes the redevelopment of organs.

10. Photodynamic therapy
Photodynamic targeting therapy refers to that with the participation of photosensitizers, under the action of light, the functional or morphological changes of organic cells or biomolecules will occur, which may lead to cell damage and necrosis in severe cases, and this effect must be accompanied by oxygen. The method of treating diseases with photodynamic action is also called photodynamic therapy (PDT). The research of targeted drugs, namely photosensitizers (photodynamic therapy drugs), is the key to affecting the prospects of photodynamic therapy. Photosensitizers are some special chemical substances whose basic function is to transfer energy, which can absorb photons and be excited, and then quickly transfer the absorbed light energy to the molecules of another component, so that they are excited and the photosensitizer itself returns to Ground state.
Application of targeted therapy in diseases: condyloma acuminatum, acne, port wine stain, tumor, etc.
Therapeutic advantages:
(1) Minimal trauma: With the help of optical fiber, endoscope and other interventional technologies, the laser can be guided deep into the body for treatment, avoiding the trauma and pain caused by thoracotomy and laparotomy.
(2) Low toxicity: Only when the photosensitizing drug enters the tissue reaches a certain concentration and is irradiated with a sufficient amount of light, it will trigger a photodynamic reaction to kill the target cells, which is a local treatment method. The parts of the human body that are not irradiated by light do not produce this reaction, and the organs and tissues in other parts of the human body are not damaged, nor do they affect the hematopoietic function. Therefore, the toxic and side effects of photodynamic therapy are very low.
(3) Good selectivity: The main target of attack is the diseased tissue in the lighted area, and the normal tissue around the lesion is slightly damaged. This selective killing effect is difficult to achieve by many other treatment methods.
(4) Good applicability: it is effective for lesions of different cell types, and has a wide range of applications; however, the sensitivity of lesions of different cell types to radiotherapy and chemotherapy may have large differences, and the application is limited.