The overall 5-year survival rate of pancreatic cancer is only 2%-3%. Surgery is the only curative treatment available, but the surgical resection rate of primary pancreatic cancer is less than 20%, the median survival is only 15-19 months, and the 5-year survival rate is only about 20%, and the local and regional recurrence rate is as high as 50%-86%. Radiotherapy is the main treatment for patients with locally advanced and distant metastatic pancreatic cancer. In recent years, with the improvement of radiotherapy technology and the application of various radiotherapy methods, the value of radiotherapy has been enhanced for both surgically resectable and non-surgically resectable locally advanced pancreatic cancer, and the current status of its application has attracted much attention. The results of a series of retrospective or prospective phase II clinical studies completed by Evans et al. in the United States did not show that preoperative induction radiotherapy could improve the survival rate of patients with pancreatic cancer after surgical resection. Kim et al. showed that conventional radiotherapy and 5-FU chemotherapy converted only 8%-13% of unresectable lesions to resectable ones, and that replacing the total (45.0-50.4) Gy at 1.8 Gy with a total of 30 Gy at 3 Gy per session shortened the preoperative course and showed similar survival curves without significantly increasing surgical mortality and complications. In 2003, Ammori et al. performed radiotherapy and gemcitabine chemotherapy in 67 patients with locally advanced disease, followed by surgical exploration in 17 patients, 9 of whom underwent Whipple surgery, with a median survival of 17.6 months after surgery, compared with 11.9 months in the group without surgery. In the phase II clinical study reported by Talamonti et al, all 20 patients with potentially surgically resectable pancreatic cancer underwent preoperative radiotherapy with 36 Gy/15 doses and concurrent chemotherapy with adequate doses of gemcitabine (1,000 mg/m2 on days 1 and 8 in 3-week cycles), and after radiotherapy, imaging suggested partial remission in 3 patients, stable lesions in 16 patients, and progression in 1 patient. Seventeen patients underwent surgical resection, of which 16 had negative margins, 1 had pathologic complete remission, and 3 had only microscopic residuals. Although only involved-field irradiation was used in this study and no prophylactic radiotherapy to the lymph nodes was administered, only 2 patients had localized regional recurrence after 18 months of follow-up. In the phase II clinical study reported by Evans et al, 86 patients with pancreatic head cancer were enrolled and treated with weekly gemcitabine monotherapy and concurrent radiotherapy at 30 Gy/10 times, resulting in 13 patients who did not undergo surgery due to disease progression or poor general condition. In the phase II clinical study reported by Varadhachary et al, concurrent chemotherapy was administered with a combination of gemcitabine and cisplatin, and radiotherapy remained at 30 Gy/10 doses. Of the 90 patients enrolled, 79 completed preoperative concurrent radiotherapy. 52 underwent pancreaticoduodenectomy. The median survival was 17.4 months for the entire group, 18.7 months for patients who received preoperative concurrent radiotherapy, 31 months for patients who underwent pancreaticoduodenectomy, and 10.5 months for patients who did not undergo surgery. A recent retrospective analysis by Stessin et al. of epidemiologic final outcome data monitored from 1994 to 2003, with the study endpoint of overall survival, found that median overall survival was 23, 17, and 12 months for patients with surgically resectable pancreatic cancer treated with neoadjuvant radiotherapy and adjuvant radiotherapy compared with those who did not receive radiotherapy, respectively. From the available phase II clinical and retrospective clinical studies, pancreatic cancer is a moderately radiation-sensitive tumor, and preoperative radiotherapy (combined with chemotherapy) is well tolerated, and its application is promising, but further confirmation is needed from multicenter randomized controlled phase III clinical studies with large number of cases. Intra-operative radiotherapy (IORT) is a treatment that involves directing high-energy electron rays generated by a high-energy gas pedal through a light-limited cylinder to the site to be irradiated, avoiding the surrounding sensitive tissues and organs, which can theoretically give a higher target dose to the tumor bed in the postoperative recurrence-prone area. + Neoptolemos et al. showed that IORT reduced the local recurrence rate by 50% without increasing surgical mortality and complications, and the high metastasis rate in the irradiated field had little impact on long-term survival. In 2001, Reni et al. analyzed the effect of IORT on different stages of pancreatic cancer. For early stage pancreatic cancer, the local recurrence rate and 5-year survival rate were 27% and 22% for those who received Whipper’s surgery + intraoperative radiotherapy, respectively, and 60% and 6% for those who did not receive intraoperative radiotherapy, which were significantly better than the latter. However, some scholars believe that intraoperative radiotherapy + external irradiation does not prolong patient survival compared with external irradiation alone, and has significant adverse effects. Although intraoperative radiotherapy can significantly reduce the local recurrence rate of pancreatic cancer, it can also lead to higher treatment complications such as peptic ulceration, perforation, duodenal fibrosis and pancreatic necrosis, and these adverse effects suggest that the single dose of radiotherapy should be limited. Intraoperative radiation therapy should not be given at doses of more than 20 Gy at a time, and the single dose should be less than 12.5 Gy in the irradiated field including the stomach or intestine. To date, many hospitals still do not have intraoperative radiotherapy facilities, and it is difficult to clarify the therapeutic effect of intraoperative radiotherapy in different pancreatic cancers in a small sample of individual studies, so it is impossible to assess the efficacy of intraoperative radiotherapy with certainty. Postoperative radiotherapy Studies over the past 30 years have shown that local regional recurrence is one of the main forms of postoperative recurrent metastases in pancreatic cancer. For patients with surgically resectable pancreatic cancer, postoperative adjuvant radiotherapy has become the standard treatment modality for surgically resectable pancreatic cancer, but it is still controversial whether adjuvant combined radiotherapy should be routinely administered after radical pancreatic cancer surgery. In 1987, the Gastrointestinal Tract Cancer Study Group (GITSG) published a landmark article on the postoperative treatment of pancreatic cancer. The results of this study showed that the median survival, 2-year and 5-year survival rates of patients randomized to 2 courses of conventional radiotherapy at a dose of 20 Gy each (i.e., 40 Gy total dose with a 2-week break between courses) combined with 5-FU chemotherapy after R0 resection were statistically higher than those of the surgery-only group, 20 months versus 11 months, 43% versus 18%, and 19% versus 5%, respectively. This was the first time that postoperative adjuvant therapy for pancreatic cancer was recognized to prolong survival. These results were further validated by American scholars, but the local recurrence rate after radiotherapy and chemotherapy in this study was as high as 30% to 50%, suggesting that the dose of radiotherapy was insufficient. In contrast to the results of the North American study, the European Organization for Research and Treatment of Cancer (EORTC) 40891 trial yielded negative results. The study randomized 208 patients with pancreatic cancer after pancreaticoduodenectomy into adjuvant radiotherapy and observation groups and showed that the median survival, 2-year and 5-year survival rates were higher in the former group than in the latter group, 17.1 months versus 12.6 months, 37% versus 23% and 20% versus 10%, respectively, but none of them reached statistical differences. Garofalo et al. re-analyzed the trial statistically and showed that adjuvant postoperative radiotherapy improved 2-year survival by 14% (from 23% to 37%) compared with surgery alone in patients with pancreatic head cancer, with a statistically significant difference (p=0.049). The European Study Group on Pancreatic Cancer1 (ESPAC-1) published a European multicenter randomized clinical study that failed to confirm the value of radiotherapy in postoperative adjuvant radiotherapy for pancreatic cancer. A total of 541 patients were enrolled in the study after pancreatic cancer resection and were randomized into observation, adjuvant chemotherapy, and adjuvant radiotherapy groups. The results showed that adjuvant chemotherapy significantly improved 2-year and 5-year survival rates, but combined radiotherapy did not show efficacy. The results were not accepted by most oncology treatment centers in North America due to the inadequate design of the study and the irregularity of the implementation process. In 2008, the American Society of Clinical Oncology (ASCO)/American Society for Radiation Oncology (ASTRO) conducted a preliminary study of RTOG-9704 comparing the efficacy of gemcitabine before and after 1 and 4 courses of standard adjuvant therapy (radiotherapy combined with concurrent 5-FU chemotherapy) for pancreatic cancer after radical pancreatic surgery. The difference between standard adjuvant therapy (radiotherapy combined with simultaneous 5-FU chemotherapy) before and after radical pancreatic cancer surgery and the addition of 1 and 4 courses of gemcitabine chemotherapy [1000 mg/(m2・week) for 3 weeks] and 5-FU chemotherapy before and after standard adjuvant therapy was compared with 50.4 Gy of radiotherapy (conventional fractionation). The results showed that the median survival and 3-year survival rates were 20.6 months and 32% for the 381 pancreatic head cancer patients treated with gemcitabine chemotherapy and 16.9 months and 21% for those treated with 5-FU, respectively, with the former being significantly better than the latter, but there was no significant effect on the prognosis of patients with pancreatic body and tail cancer. The median survival, 2-year survival, and 5-year survival rates were 25.2 months, 50%, and 28% for those who received postoperative adjuvant radiotherapy (50.4 Gy/28F, 98% of cases received 5-FU-based concurrent chemotherapy) and 19.2 months, 39%, and 17% for those who did not receive postoperative adjuvant radiotherapy, respectively, which were significantly better than the latter in the study by Herman et al. The median survival, 2-year survival, and 5-year survival rates were 21.2 months, 43.9%, and 20.1%, respectively, for those who received postoperative adjuvant radiotherapy, compared with 14.4 months, 31.9%, and 15.4% for those who did not receive postoperative adjuvant radiotherapy. The results of the combined study by Hsu et al. The majority of the literature suggests that postoperative radiotherapy improves overall survival compared to chemotherapy alone, and the combination of radiotherapy with gemcitabine improves tumor-free survival, recommending the combination of chemotherapy with radiotherapy containing gemcitabine as an adjuvant treatment modality for patients with surgically resected pancreatic cancer. Currently, the Radiation Therapy Oncology Group (RTOG) led studies on adjuvant treatment of pancreatic cancer still use combination radiotherapy as the standard treatment modality. Combination radiotherapy is the standard adjuvant therapy after pancreaticoduodenectomy (Ro), and adjuvant combination radiotherapy should be considered after radical surgery for locally advanced pancreatic cancer (LAPC). In view of the fact that the survival of patients who received only R2 resection is the same as those who received only combined radiotherapy without radical surgery, patients with incomplete surgical resection of pancreatic cancer should also receive combined radiotherapy after surgery, but the specific plan should refer to the treatment strategy for inoperable patients. Early clinical studies have shown that radiotherapy alone is a good palliative treatment for pain and obstructive symptoms in patients with locally advanced pancreatic cancer (LAPC), and compared with the best supportive symptomatic treatment, radiotherapy alone can also prolong the survival of patients with locally advanced inoperable pancreatic cancer. Currently, gemcitabine-based concurrent radiotherapy is one of the standard recommended treatments for locally advanced inoperable pancreatic cancer. However, even so, the therapeutic value of radiotherapy in this type of pancreatic cancer is still controversial. In a randomized clinical study completed by the Gastrointestinal Tumor Study Group (GITSC) in 1981, conventional radiotherapy at a total dose of 40 Gy or 60 Gy combined with concurrent 5-FU chemotherapy significantly prolonged median survival compared to radiotherapy alone (8.3 months versus 11.3 months versus 5.5 months). The median survival and survival rates in the group receiving the combination of streptozotocin, mitomycin and 5-FU (SMF) regimen chemotherapy + radiotherapy were inferior to those of patients receiving 5-FU single agent combined with radiotherapy. Therefore, the treatment of inoperable pancreatic cancer has long been based on simultaneous 5-FU monotherapy combined with conventional external radiotherapy. Chauffert et al. compared the efficacy of combined radiotherapy and chemotherapy alone in patients with locally advanced inoperable pancreatic cancer and found negative results, i.e., combined radiotherapy was not superior to chemotherapy alone, but even had a negative effect on survival compared to chemotherapy alone. Due to the high dose of radiotherapy (60 Gy ) in this study and the overly intense chemotherapy regimen (5-FU combined with cisplatin) in simultaneous radiotherapy, the incidence of grade III-IV adverse effects was so high that it was prematurely closed after the initial report. The efficacy of gemcitabine in combination with radiotherapy for inoperable locally advanced pancreatic cancer has been supported by the results of clinical studies. 2007 Hugliet et al. reported a phase II-III clinical study in which patients with locally advanced inoperable pancreatic cancer received gemcitabine-based chemotherapy for 3 months, and after chemotherapy was completed, patients with good general condition and no tumor progression were treated with concurrent radiotherapy. The results showed that the median survival was 15 months for those who received radiotherapy and 11.7 months for those who did not receive radiotherapy, while the median survival was only 4.5 months for those who received gemcitabine-based chemotherapy with disease progression. To better define the role of radiotherapy in the management of locally advanced inoperable pancreatic cancer, Huguet et al. conducted a qualitative systematic review of radiotherapy in patients with locally advanced inoperable pancreatic cancer. The results showed that in patients with locally advanced inoperable resected pancreatic cancer, combination radiotherapy or chemotherapy alone prolonged overall survival compared with best supportive symptomatic therapy; in terms of overall survival, combination radiotherapy was not superior to chemotherapy alone and increased the corresponding adverse effects. Thus, it is concluded that although there is no gold standard for the treatment of locally advanced inoperable resectable pancreatic cancer, two treatment options are available, namely gemcitabine-based chemotherapy or gemcitabine-based radiotherapy. A randomized study in Taiwan, China, in 2003 compared the efficacy of simultaneous chemotherapy based on 3-dimensional conformal irradiation, 5-FU, with that of gemcitabine. The results showed that the gemcitabine radiotherapy group had a significantly higher response rate (50% vs. 12.5%, P=0.005), median time to progression (7.1 months vs. 2.7 months, P=0.019) and median survival (14.5 months vs. 6.7 months, P=0.027) than the 5-FU radiotherapy group. In 2008, Small et al. completed a prospective phase II clinical study in which 39 patients with progressive pancreatic cancer of different stages received standard dose (1,000 mg/m2 ) of gemcitabine chemotherapy combined with three-dimensional conformal radiotherapy (3D-CRT) at a total dose of 45 Gy. The results showed that the combination of radiotherapy significantly improved the prognosis of patients, with 1-year overall survival rates of 94%, 76% and 47% for patients with complete resection, critical unresectable and unresectable cancer, respectively. Another Korean study also used 3D-CRT (total dose 45 Gy) in combination with standard dose gemcitabine in 41 patients with inoperable progressive pancreatic cancer, with 1-year and 2-year overall survival rates of 63.3% and 27.9%, respectively. The results of a phase III randomized clinical study (E4201) completed by the Eastern Cooperative Oncology Group (ECOG) in the United States further showed that simultaneous adjuvant treatment with a total dose of 50.4 Gy of radiation therapy combined with gemcitabine [600 mg/ (m2/week) for 6 weeks] significantly prolonged survival compared with gemcitabine chemotherapy alone. In addition, a phase II clinical study completed by Saif et al. in 2007 showed that 1 600 mg/ (m2・d) of capecitabine (days 1-5 for 6 weeks) combined with concurrent radiotherapy (50.4 Gy, conventional fractionation) followed by adjuvant capecitabine 2 000 mg/ (m2・d) for 2 weeks plus 1 week of rest was a course of treatment until tumor progression, with 20% of patients in partial remission and 65% with stable disease after completion of combined radiotherapy. The overall survival rate at 1 year was 58%. Based on the best known clinical evidence, it is recommended that patients with inoperable pancreatic cancer be considered for treatment with gemcitabine in combination with 3D-CRT or intensity-modulated radiation (IMRT). Simultaneous combination radiotherapy based on capecitabine or 5-FU may still be considered for patients who cannot receive gemcitabine. Although simultaneous combination radiotherapy is more effective than monotherapy, the dose of radiotherapy for pancreatic cancer is limited due to the deep pancreatic site and the proximity to vital organs, usually between 45 and 54 Gy. High doses of conventional external radiotherapy (including 3D-CRT) can lead to serious adverse effects when used in combination with gemcitabine chemotherapy. The dose limitation of radiotherapy is currently considered as one of the main factors of poor efficacy after adjuvant radiotherapy and “radical” radiotherapy for pancreatic cancer, and with the continuous development of radiotherapy techniques such as adaptive radiotherapy (ART) and image-guided radiotherapy (IGRT), the locally acceptable dose of tumor will be increased. In addition, advocating a multidisciplinary and integrated treatment strategy is also the development direction to further improve the overall efficacy of progressive pancreatic cancer. V. Other radiotherapy methods In 1989, the RTOG Study Group reported a randomized group study of neutron therapy for locally advanced inoperable resectable pancreatic cancer, which had no significant advantage over conventional radiotherapy. In view of the insignificant effect of neutron therapy on prolonging survival and the serious complications of intractable peptic ulcers, few studies on neutron therapy for pancreatic cancer have been conducted in Europe and the United States in recent years. Percutaneous percutaneous iodine 125 particle implantation or intraoperative particle implantation radiotherapy has a certain effect on prolonging survival and is effective in relieving pain, but due to the complexity of the technique and the problem of precise localization, as well as the frequent complications of gastrointestinal bleeding, pancreatitis and pancreatic fistula, it is only used in a few hospitals and there are no clinical reports of large samples of cases. After more than half a century of surgical resection-oriented treatment of pancreatic cancer, the poor efficacy and little progress have shown that the special anatomical site and biological characteristics of pancreatic cancer limit the role of surgery. With the advancement of modern radiotherapy techniques and improved therapeutic efficacy, the use of local radiotherapy + chemotherapy or drug-targeted therapy, which is less invasive and more effective in pancreatic cancer, deserves further in-depth study to achieve better therapeutic results.