Primary liver cancer is the sixth most common malignancy (626,000 new cases per year), the most prevalent in Asia and South Africa, and the third leading cause of cancer death worldwide (598,000 deaths per year), with 5-year survival rates remaining at only 3-5% to date. From 1991 to 2006, the number of deaths from hepatobiliary tumors increased by 30%. The American Association for the Study of Liver Diseases considers surgical resection and liver transplantation as two potentially curative approaches to achieving long-term disease-free survival. Radical resection of hepatocellular carcinoma has a 5-year survival rate of up to 50%, but is often accompanied by a high recurrence rate. The recurrence rate is about 40%-50% at 3 years after surgery, and the 5-year metastatic recurrence rate is about 60%-70%. Therefore, for patients who cannot undergo liver resection and liver transplantation, other treatment modalities are playing an increasingly important role. At present, non-surgical treatments for liver cancer include percutaneous ethanol injection (PEI), radio frequency ablation (RFA), transarterial chemoembolization (TACE), radiation therapy, and hepatic artery embolization. (TACE), Radiation therapy (RT) and targeted therapy. Among the non-surgical methods, PEI, RFA and TACE are not effective enough for inoperable hepatocellular carcinoma, and targeted drugs such as sorafenib are expensive and have large cardiovascular side effects, which are not tolerated by patients, while radiation therapy directly targeting the liver lesion has the potential to improve local control rate, survival and quality of life. This article is a review of radiation therapy for liver cancer. 1. History of radiotherapy for liver cancer Since the 1920s, radiotherapy for liver cancer has been explored in North America and Europe, but primary liver cancer is a rare tumor in Europe and America, while metastatic liver cancer is more common, so radiotherapy is applied to the treatment of metastatic liver cancer. However, the experience of radiotherapy for primary liver cancer is almost zero, and radiotherapy has basically no status in the treatment of primary liver cancer. Domestic attempts on radiotherapy began in the 1950s and 1960s, when it went through variations such as whole liver large field irradiation, local irradiation, whole liver mobile strip field irradiation, and hyper-segmentation radiotherapy. In 1963, Wei-Be Yin found that the average survival of patients with liver cancer treated with radiation therapy was higher than that of the untreated group. During this period, radiotherapy was mostly applied to a large area, half or even the whole liver, with serious liver damage and extremely poor efficacy. Subsequently, radiotherapy developed into localized tumor area irradiation, and the efficacy improved, but side effects such as radioactive hepatitis were still not uncommon. Whole liver mobile strip field irradiation was first designed to prevent abdominal metastasis of ovarian cancer, and later extended to whole liver and whole lung irradiation. However, some scholars have pointed out that “mobile strip irradiation has serious shortcomings in both theory and practice”. Although whole liver mobile strip irradiation improves the tolerated dose of the liver, it is difficult to achieve tumor control due to long treatment period, splitting of irradiation field on the tumor and uneven dose distribution within the tumor, so radiotherapy was once discarded from the treatment of liver cancer. Therefore, in the 1980s, radiation therapy for liver cancer almost disappeared. 2.Tolerable dose of radiotherapy for liver cancer Primary liver cancer was once regarded as a radiation-resistant tumor, and radiotherapy could hardly be effective. In 1987, the University of Michigan started to study the relationship between radiation therapy dose and primary liver cancer, and conducted partial liver conformal radiotherapy for 204 patients with the highest dose of 90Gy (1.5-1.65Gy /Ben-Josef et al. reported a radiation tolerance dose of up to 90 Gy when irradiating only part of the liver volume. In recent years, with the application of 3D conformal radiotherapy, intensity modulated radiotherapy, stereotactic radiotherapy and heavy ion proton radiotherapy, the tolerated dose to the liver has been increased and the volume of the liver irradiated has been reduced, thus reducing the incidence of RILD. V30 (the volume of the liver irradiated by 30Gy dose) ≤ 60% of the whole liver volume. 3. Radiotherapy status of hepatocellular carcinoma There are several staging methods for hepatocellular carcinoma, but only Barcelona staging (BCLC staging) organically combines tumor location, size and liver function with the patient’s general condition, and provides guidance recommendations for the treatment of hepatoCellular carcinoma (HCC). Less than 30% of patients diagnosed with primary hepatocellular carcinoma are in the early stage, 20% are in the advanced stage for which palliative therapy is recommended, and the remaining 50% are in incurable locally advanced or metastatic disease that can be treated locally or systemically. However, radiation therapy, as one of the three major treatments for tumors, is not mentioned in the BCLC staging, so is there really no place for radiation therapy in liver cancer treatment? The answer is certainly not. There is more and more evidence that radiotherapy has a role in the treatment of HCC, and stereotactic radiotherapy or external radiation conformal therapy may be used for tumors in any location. 4. Reconceptualizing the efficacy of radiation therapy for hepatocellular carcinoma 4.1 Small hepatocellular carcinoma Mornex F et al. evaluated the feasibility and effectiveness of three-dimensional conformal radiation therapy for hepatocellular carcinoma in a French phase II prospective trial. 27 patients with liver function Child-Pugh grade A or B, with a single lesion ≤125px or two ≤75px, were treated with a total radiation dose of 66 Gy and a single dose of 2 Gy. 25 cases patients completed radiotherapy as planned with an efficiency of 92% (80% for CR and 12% for PR). The median follow-up period was 29 months, and the local control rate in the radiation field was 78%. 3 (19%) of Child-Pugh class A patients had grade 3 side effects and no grade 4 or higher injury. 3 (27%) of Child-Pugh class B patients had grade 4 acute side effects. the results reported by Kim TH et al. were similar to this study. Guangxi Medical University Cancer Hospital applied 3-DCRT technique to treat 28 patients with hepatocellular carcinoma ≤125px in diameter, with an overall effective rate of 96% (CR59%, PR37%) and good survival rates of 100%, 85% and 60% at 1, 2 and 3 years, respectively. In the Armed Police General Hospital [18], SBRT was applied to treat 22 cases of small hepatocellular carcinoma, with an overall effective rate of 72.73% (16/22) and cumulative survival rates of 81.2%, 68.7% and 62.4% at 1, 2 and 3 years, respectively. The median survival time was 40.0 months. In contrast, the current 3-year survival rate of surgical treatment of small hepatocellular carcinoma (diameter ≤125px) is about 70%, which shows that the efficacy of radiation therapy is gradually improving, and its role is even inferior to that of surgery in some clinical cases. 4.2 Large hepatocellular carcinoma In China, large hepatocellular carcinoma predominates, and about 80% of patients have already lost the opportunity of surgery when diagnosed, and 85% of them are combined with cirrhosis, which makes them unable to tolerate hemihepatectomy. Hsiao-Ping Chen has reported that the cumulative survival rates of large liver cancer at 1, 3, 5 and 10 years after surgery were 66.1%, 32.7%, 12.2% and 2.3%, respectively. In Taiwan, 44 patients with large hepatocellular carcinoma (6-625 px) were treated with 40-60 Gy of radiotherapy, with an overall efficiency of 61% and no toxic side effects of grade 3 or higher. wU D et al. performed 3D conformal radiotherapy on 93 patients with large hepatocellular carcinoma of 5-450 px in diameter, and the efficiency was 91%, and the 1-year and 3-year survival rates were 94% and 26%, respectively. It can be seen that radiotherapy achieves similar efficacy in the treatment of large hepatocellular carcinoma compared with surgery and various minimally invasive means. 4.3 Advanced hepatocellular carcinoma combined with vascular cancer embolism In order to release the embolism, reduce the portal pressure, and even achieve the goal of reducing intrahepatic metastasis, certain studies have targeted radiation therapy for portal vein cancer embolism. In a large trial in Taiwan, 326 patients with portal vein cancer embolism were treated with a total dose of 60 Gy of radiation therapy, with a single 2-3 Gy, and the final efficiency was 25%, and the 1-year survival rate was 17%. Kumamoto University, Japan, reported the results of a trial of 38 patients with portal vein cancer embolism who received 30 Gy irradiation dose including the primary tumor to <30% of the liver volume. The total radiation dose ranged from 17.5-50.5 Gy at 1.8-4 Gy/dose, with a bioequivalent dose of 23.4-59.5 Gy. The overall effective rate was 45%, and the 1-year survival rate was 39%. The size of the cancer thrombus and the dose of radiotherapy predicted the effective rate (80% for BED ≥ 58Gy; only 22% for BED < 58Gy), but the survival rate was correlated with the dose of radiotherapy (59% 1-year survival rate for BED ≥ 58Gy; 29% 1-year survival rate for BED < 58Gy) and Child-Pugh classification (51% 1-year survival rate for grade A patients and 0% for grade B patients). Princess Margaret Hospital [24] used SBRT to treat 41 patients with hepatocellular carcinoma (31 HCC), nearly half of whom had portal or other large-vessel cancer thrombosis, and the dose was individualized according to the NTCP (Normal Tissue Complication Probability) The dose was individualized according to the NTCP (Normal Tissue Complication Probability) model, with a median dose of 36 Gy (24-54 Gy), a median tumor volume of 173 mL (9-1913 mL), a number of fractions of 6, and a total duration of 2 weeks. 26% of patients experienced 3rd degree liver enzyme elevation and 16% deteriorated from Child-Pugh grade A to grade B during the 18-month follow-up period, but no typical RILD occurred. As a result, 5% achieved CR, 44% achieved PR, and 42% remained in SD status, with a median survival of 11.7 months. In contrast, surgery for large-vessel cancer thrombosis is not ideal [25], so radiotherapy may be the only effective method for patients with inoperable hepatocellular carcinoma combined with vascular cancer thrombosis. 5. Combination of radiotherapy with other treatments In the liver, there is a risk of disseminated nodules and regional metastasis outside the irradiated liver volume, and higher radiation dose and larger radiotherapy area may lead to RILD, so whether there are other treatments to combine radiotherapy to achieve both local and regional efficacy is beginning to enter the research field. In order to reduce the toxic side effects of radiotherapy, low-dose radiotherapy is usually used in combination with TACE, and there are two ways to combine radiotherapy with TACE, the first one is to use radiotherapy to remove the portal vein and inferior vena cava thrombus before TACE to improve the efficacy of TACE. slightly larger tumor diameter (325px vs 250px), radiotherapy combined with TACE was more effective (43% vs 14%) and overall survival was longer (11.7 vs 4.7 months). Cupino AC et al. divided 44 patients into two groups, TACE alone (37 patients) and TACE sequential EBRT (7 patients), and the survival without organ transplantation was 376 days in the TACE alone group and 376 days in the TACE sequential EBRT group. Kang JK [28] et al. administered SBRT after 1-5 TACE sessions in 47 patients (41 Child A, 6 B grade, 5 with portal vein carcinoma thrombosis) at doses of 42-60 Gy/3F with a median tumor diameter of 29 mm (13-78 mm), and evaluated the efficacy after 6 months, 18 cases (38.3%) CR, 18 (38.3%) PR, 2-year local control rate of 94.6%, overall survival rate of 68.7%, and progression-free survival rate of 33.8%.Yoon et al [29] conducted a retrospective study of 412 patients with portal vein cancer embolism who underwent TACE combined with 3-DCRT at a dose split of 40Gy (21-60Gy)/2-5F,CR3.6%, PR24.3%, median survival 10.6 months, 1-year and 2-year survival rates of 42.5% and 22.8%, respectively.University of Virginia [30] performed radiotherapy combined with simultaneous capecitabine sensitization in 20 patients with a mean tumor diameter of 225px (1.3-434.9999999999999994px) at a split dose of 50Gy/20f with a 3- Studies on whether the combination of other targeted drugs (e.g., sorafenib) and radiotherapy can improve the efficacy of hepatocellular carcinoma are also underway. 6. Advances in radiotherapy technology The reason why radiotherapy is more and more widely used in the treatment of liver cancer is, ultimately, inseparable from the development of radiotherapy technology. Historically, because of the low tolerated dose of liver radiotherapy, patients often faced the risk of radiotherapy-induced hepatotoxicity, but there was no significant benefit from giving only small doses of radiotherapy, and radiotherapy was rarely used in liver cancer treatment. In the last decade, with the high development of computer technology and its application in the medical field, the latest technology of radiotherapy - 3D conformal radiotherapy and intensity-modulated radiotherapy - has been generated and developed. Therefore, it is possible to try to treat liver cancer with radiotherapy again. 3D conformal radiotherapy can make the shape of the irradiation field basically consistent with the shape of the tumor target area, i.e. conformal, so as to increase the local irradiation dose to the tumor while minimizing the irradiation dose to the surrounding normal liver tissues and organs, thus achieving the requirements of precise target location and accurate treatment. The 3-year survival rate of liver cancer patients after 3DCRT/IMRT radiotherapy is 28%~33%. The incidence of hepatocellular carcinoma in Asia is much higher than that in the United States, and there is more experience with radiotherapy. Seong J et al [31] reported a multicenter retrospective study of 398 primary hepatocellular carcinoma patients treated from 10 medical institutions in Korea, with 72% of patients in Child-Pugh grade A, 54% with tumor diameter >125px, 40% with portal vein cancer embolism, and 90% of patients who had received other treatments, mainly Sixty-two percent of patients had a total radiotherapy dose of ≥45 Gy and a single dose of 1.8-5.0 Gy. Nine percent of these patients failed to complete radiotherapy because of poor systemic status. Multifactorial analysis showed that a bioequivalent dose (BED) ≥53.1 Gy improved 2-year survival (31% vs. 22%). Guangxi Medical University treated 128 patients with primary liver cancer from 1999 to 2003, 84% of Child-Pugh grade A patients with a median radiation dose of 54 Gy (38-68 Gy) and a single split dose of 4-Gy, with a local control rate of 69% at 3 months after the end of radiotherapy and overall survival rates of 65% and 33% at 1 and 3 years, respectively. Zeng Zhaochong et al. pointed out that radiation hepatitis is more often seen with conformal radiotherapy because conformal radiotherapy is used to achieve the goal of uniform dose in the target area, while the surrounding normal liver tissues are irradiated with unequal doses and the regenerative ability of hepatocytes is affected. Stereotactic radiation therapy (SBRT), which can better preserve some liver tissues from radiation, is gradually emerging as the frontline of treatment, and it refers to the central technique such as stereotactic radiation therapy to concentrate the radiation on the lesion for high-dose irradiation. The first prospective trial of SBRT for liver cancer was conducted by Mendez-Romero [34] in 25 patients with primary liver cancer (8 patients with primary liver cancer). patients (8 primary hepatocellular carcinoma, 6 Child-Pugh grade A, 2 Child-Pugh grade B) with SBRT. The radiation dose was 37.5 Gy/3 doses in patients without cirrhosis and cirrhosis with tumor diameter <100 px, and 25 Gy/5 doses were initially given to patients with cirrhosis with tumor diameter ≥100 px, but local progression occurred in 2 cases, so the dose was The 1-year local control rate was 75% (treatment failure in the 25Gy group) and the 1-year survival rate was 48%. Some large studies of SBRT for primary liver cancer have also been conducted in Asia and Europe.Kwon et al [35] reported a high treatment efficiency (CR 60%, PR 26%) and progression-free survival rates of 72% and 68% at 1 and 3 years, respectively, in 42 patients with HCC treated with SBRT at a radiotherapy dose of 30-39Gy/3f.Seo et al [36 ] applied SBRT to treat 38 patients with HCC at a dose split of 33-57 Gy/3-4f and achieved a local control rate of 79% and an overall survival rate of 68% during a median follow-up period of 15 months. Multifactorial analysis showed that radiotherapy dose was an independent prognostic factor, with a 2-year survival rate of 81% in patients with doses ≥42Gy/3f and only 25% in the remaining patients. A French group [37] reported the results of 25 HCC patients who received 45 Gy/3f irradiation with a 1-year local control rate of 95% (median follow-up period 13 months).Stenmark et al [38] performed SBRT in 31 HCC patients with a tumor volume of 0.2-222.4 cc at a dose of 50 Gy/5 or 60 Gy/3 times, with a 1-year local control rate of 88% and 1-year survival rate of 81%. Therefore, although the history of SBRT application is not long, and the treatment targets are small single lesions, it can achieve a better local control rate, and the 1-year survival rate is about 70%-90%, so it can be said that the efficacy of radiation therapy is not inferior to surgery. 7.Precision liver stereotactic radiotherapy surgery concept with the concept of precision liver resection The surgical treatment of primary liver cancer has gone through the stages of wedge liver resection, regular liver lobectomy, local liver resection and anatomical liver segment resection, etc. With the progress of science and technology, the current liver surgery aims to obtain the best recovery with the least trauma, that is, to ensure the complete removal of the target lesion, maximize the protection of the remaining liver This is to ensure the complete removal of the target lesion while maximizing the protection of the remaining liver and minimizing the surgical trauma to achieve the goal of precise liver resection. With this surgical concept, radiotherapy has also been revitalized. Like the concept of precise liver resection, 3D conformal or intensity-modulated radiotherapy is a new method to achieve the best recovery with minimal trauma (complete destruction of the target area, maximum protection of the remaining liver, and minimum radiotherapy damage). The efficacy of radiotherapy is comparable to that of surgery for small hepatocellular carcinoma in the middle stage and that of surgery for large hepatocellular carcinoma, which is worth further promotion and perfection. Thus, the role of radiotherapy in the treatment of liver cancer cannot be ignored.