Radiotherapy is one of the basic means of malignant tumor treatment, but before the 1990s, patients with primary liver cancer (PLC, hereafter referred to as hepatocellular carcinoma) were less likely to receive radiotherapy because of its poor effectiveness and greater damage to the liver. after the mid-1990s, modern radiotherapy techniques such as three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated conformal radiotherapy (IMRT) have gradually matured, providing new opportunities for The application of radiotherapy in the treatment of liver cancer has provided new opportunities. Currently, studies have been published on the use of 3DCRT and IMRT for the treatment of primary hepatocellular carcinoma that cannot be surgically resected. For patients with hepatocellular carcinoma confined to the liver, the 3-year survival rate of radiotherapy combined with interventional therapy has reached 25%-30%. Indications for radiotherapy for hepatocellular carcinoma 1. The tumor is confined, cannot be surgically resected due to poor liver function, or the tumor is located in an important anatomical location and cannot be technically resected, or the patient refuses surgery. The general condition of the patient is good, such as KPS (quality of life score) ≥ 70. 2.There are residual lesions after surgery. 3, Local oncologic management is required, otherwise some complications may arise, such as radiotherapy for bile duct obstruction, tumor emboli in portal and hepatic veins. For patients with bile duct obstruction, drainage can be performed first to relieve jaundice, and then radiotherapy can be performed. 4. For distant metastases, such as lymph node metastases, adrenal metastases and bone metastases, radiotherapy can alleviate patients’ symptoms and improve their quality of life. Techniques of radiotherapy for liver cancer Radiotherapy dose splitting The existing clinical experience shows that large splitting radiation, such as 5 Gy per time, once a day, three times a week, with a total dose of about 50 Gy, has a strong killing effect on tumor, but the radiation damage to the normal liver is also large. Conventional split radiation, such as 2 Gy/time, once a day, 5 times a week with a total dose of 50~62 Gy, has a significant tumor suppression effect and is better tolerated by the normal liver. If hypofractionated conformal radiotherapy with 4~8 Gy/dose is used, more than 70% of patients will die from liver failure in a short period of time once radioactive liver injury occurs. However, further clinical studies are needed to prove which segmentation method is better. Radiotherapy plan 1. Radiotherapy technique: The results of dosimetric comparison show that IMRT radiotherapy has better dose conformability in the target area and a smaller irradiated dose in the normal liver compared with 3DCRT. IMRT is more suitable for patients with large hepatocellular carcinoma that exposes normal liver tissue to larger doses or patients who cannot tolerate large doses due to severe cirrhosis. 2.Control of respiration: It is recommended to use respiration control techniques such as Active Breath Control Regulator (ABC) to limit the movement of tumor in radiotherapy so as to reduce the radiation dose to normal liver. 3.Target area localization: In order to improve the accuracy of the general tumor extent (GTV) outline of liver cancer, it is recommended to use arterial phase for CT, because most of the liver cancers belong to arterial blood supply; however, when determining venous cancer thrombi, venous phase must be used, and arterial phase can be used as a reference, because some cancer thrombi also have arterial blood supply. When outlining on magnetic resonance imaging (MRI), T2 phase is recommended for intrahepatic lesions; fusion techniques of CT and MRI images are also recommended to improve the accuracy of GTV outlining. Combined with the iodine oil deposition images after interventional embolization chemotherapy (TACE) can identify the tumor target area. In practice, it is important to allow sufficient margin when determining the GTV of hepatocellular carcinoma, as many patients have tumors that are not well defined on CT and MRI images. The clinical tumor volume (CTV) is GTV plus 4 mm; the planned radiotherapy target area (PTV) extends 5-10 mm from CTV (depending on different hospitals); therefore, the extents from GTV to PTV should be 10-15 mm. Of course, if the radiation dose to the liver exceeds the tolerance range, a reduction of the extents can be considered in order to enable radiotherapy to be performed. The PTV is CTV plus 6 mm under the condition of using ABC device, and it is more determined by the patient’s respiration when ABC is not used. Currently, there are units that perform 2 courses of TACE prior to radiotherapy, with an interval of 3-6 weeks, followed by an evaluation to determine the need for radiation therapy. This protocol may have the following benefits: (1) small liver cancer lesions can be detected and treated during TACE; (2) it facilitates the identification of tumor target areas; and (3) it facilitates the verification of the radiotherapy plan before its completion. Complications of radiotherapy Complications of radiotherapy for primary liver cancer include liver injury in the acute phase (during radiotherapy) and in the late phase of radiotherapy (within 4 months). Acute toxicities The main toxicities during radiotherapy include: 1. anorexia, nausea, vomiting and, in more severe cases, upper gastrointestinal bleeding, especially in patients with large volumes of duodenum, jejunum and stomach involved in the radiation field; 2. acute hepatic impairment, manifested by increased serum bilirubin and alanine transaminase (ALT); 3. bone marrow suppression, especially in patients with large volumes of liver irradiated or with hypersplenism Patients with hypersplenism. The main late radiation injury is radiation-induced liver disease (RILD). It has the following clinical manifestations and diagnostic criteria: 1. having received high-dose radiotherapy to the liver; 2. occurring after the end of radiotherapy; 3. having two types of clinical manifestations: typical RILD has a rapid onset, with patients rapidly developing massive ascites and liver enlargement within a short period of time, accompanied by an increase in alkaline phosphatase (AKP) to more than twice the normal value or an increase in ALT to more than five times the normal value; atypical RILD has only liver function Atypical RILD only has impaired liver function, with AKP elevated to more than 2 times the normal value, or ALT elevated to more than 5 times the normal value, without liver enlargement and ascites; 4. Clinical symptoms and liver function impairment caused by liver tumor development, after radiotherapy or intervention, drug-related liver disease or viral hepatitis activity can be excluded. Treatment of RILD is symptomatic and includes the use of adrenocorticosteroids, diuretics, along with aggressive hepatoprotective drugs and supportive therapy.RILD is a serious radiation complication that, when it occurs, can cause liver failure with a high mortality rate. The most critical measure to avoid the occurrence of RILD is to strictly limit the dose of radiation to the normal liver within the tolerable range when designing the radiotherapy plan. According to our data, the tolerated dose (whole liver average dose) to the liver may be 23 Gy in Child-Pugh class A patients and 6 Gy in Child-Pugh class B patients, and this conclusion comes from radiotherapy with large fractions, i.e., 4-6 Gy per session, 3 irradiations per week, and a total dose of about 50 Gy. Patients who are prone to RILD, such as those with pre-existing poor liver function (Child-Pugh class B), large irradiated volume of normal liver, high dose, and short interval between radiotherapy and TACE combination therapy of less than 1 month, should be treated with more caution. In addition, patients who develop acute hepatic impairment such as liver injury ≥ RTOG grade II during radiotherapy have a 60% chance of developing RILD later if radiotherapy is continued. Acute liver injury is often reversible and easily repaired, while late liver injury is often irreversible and is a serious radiation injury with high mortality once it occurs. Summary In the treatment of PLC, radiotherapy can be applied in the following cases. ● hepatocellular carcinoma confined to the liver: the combination of radiotherapy and intervention has the potential to delay local dissemination within the liver and significantly improve efficiency and survival, with evidence-based medical evidence grade C; ● hepatocellular carcinoma with cancer embolism: radiotherapy for cancer embolism developed after surgical or interventional treatment and for cancer embolism in the primary focus (including inferior vena cava cancer embolism) can prolong patient survival, with evidence-based medical evidence grade C; ● hepatocellular carcinoma with lymph node metastasis: radiotherapy significantly improves survival in patients with hepatocellular carcinoma with lymph node metastasis. Intrahepatic cholangiocarcinoma: radiotherapy can prolong the survival of patients with residual cancer at the cut edge after resection and unresectable intrahepatic cholangiocarcinoma, and the evidence-based medical evidence is grade C. Most of the above-mentioned radiotherapy for PLC is palliative in nature, with poor efficacy and prolonging survival, if at all, by only a few months, but since other treatments have also failed to show better efficacy and stronger evidence-based medical evidence, radiotherapy remains one of the important treatments to be considered, especially for extrahepatic metastatic lesions.