1.Progress in surgical treatment of pancreatic cancer After decades of development, pancreatic cancer surgery has become quite mature, and its surgical indications and operations have not undergone any revolutionary changes in recent years. Recent advances are mainly focused on improving the safety of surgery and improving the long-term prognosis. (1) Progress of pancreaticoduodenectomy Pancreaticoduodenectomy (PD) is a routine surgical procedure for pancreatic head cancer. In recent years, there have been more improvements in surgical approaches, such as the superior mesenteric artery approach [1], hooked approach [2], and posterior approach [3]. Although there are differences between these approaches, they all emphasize the exploration of the superior mesenteric artery (SMA) and the complete and integral resection of the pancreatic mesentery. The main advantages of these approaches are the early and reliable determination of whether the tumor invades the SMA, portal vein-superior mesenteric vein (PV-SMV), the resectability of the tumor and the need for combined PV-SMV resection. In addition, the above approach is more in line with the principle of tumor-free, avoiding the compression of the tumor during the resection of the leptomeninges in the classical PD procedure, and at the same time, facilitating the contouring of the nerve and lymphatic tissue on the right side of the SMA and improving the rate of radical resection of the tumor. (2) Progress of pancreatic tail resection Distal pancreatectomy (DP) is the conventional surgical treatment for pancreatic tail cancer. The most representative one is radical antegrade modular pancreatosplenectomy (RAMPS), in which the neck of the pancreas is first cut, the splenic artery is cut by root ligation, the abdominal trunk (N9) and the left lymph node of the superior mesenteric artery (N14) are removed, and then the left side of the pancreas is completely resected along the surface of the left renal vein. The whole tissue including the caudal part of the body, the spleen and the left anterior renal fascia was removed. The advantage of this procedure is that it can clear more lymph nodes and reduce the probability of positive margins, which ultimately reduces the local recurrence rate of the tumor and improves the long-term survival of patients [4-8]. At present, the status of gemcitabine as the “gold standard” in pancreatic cancer chemotherapy has been unshakable, and both NCCN guidelines and ESMO guidelines recommend gemcitabine as the first-line chemotherapy drug. In most of the clinical studies conducted so far, gemcitabine is also used as a control drug. In recent years, multiple gemcitabine-based chemotherapy combinations for the treatment of advanced pancreatic cancer, including the combination of fluorouracil, cisplatin, oxaliplatin, capecitabine, irinotecan, doxorubicin, docetaxel and pemetrexed, have failed to significantly improve the overall survival of patients, and the application of some novel drugs has produced some improvement in the outcome of pancreatic cancer endotherapy, as described below. (1) Albumin-bound paclitaxel combined with gemcitabine regimen chemotherapy improved the treatment outcome of advanced pancreatic cancer Albumin-bound paclitaxel is a new generation of targeted paclitaxel agent, mainly using nanotechnology to bind paclitaxel to human blood albumin into gelatinous suspension particles with an average diameter of 130 nm [9]. The improved dosage form improves the aqueous solubility of paclitaxel and alters the original pharmacokinetics, with faster dissolution, earlier peak time of free paclitaxel concentration, and faster distribution to tissues. In addition, the drug was found to significantly reduce the fibrous component of the tumor mesenchyme and increase the endothelial cellular component of the tumor mesenchyme, thereby increasing the concentration of the drug within the tumor cells [10]. All these may be the reasons for the superior effect of albumin-bound paclitaxel over conventional paclitaxel. In a phase I/II clinical regimen of albumin-bound paclitaxel combined with gemcitabine, 44 patients with advanced disease taking 125 mg/m2 albumin-bound paclitaxel combined with 1000 mg/m2 gemcitabine for 1 cycle of 4 weeks achieved a median overall survival (mOS) and median progression-free survival (mPFS) of 12.2 and 7.9 months, respectively [10]. Compared with single-agent gemcitabine, the combination chemotherapy group had a significant survival advantage in mOS (8.7 months vs. 6.6 months), and in addition, the 3-year survival rate was 4% in the combination chemotherapy group compared with 0 in the single-agent gemcitabine group [11]. 2013 US NCCN guidelines have recommended albumin-bound paclitaxel in combination with gemcitabine as a class of evidence for the treatment of metastatic pancreatic cancer, and 2015 The 2015 NCCN guidelines recommended this regimen as a neoadjuvant treatment option for patients with borderline resectable pancreatic cancer (BRPC). (2) Tegeo single-agent oral regimen is not inferior to gemcitabine single-agent chemotherapy Tegeo (S-1) is a compounded oral anticancer drug that has been explored in recent years in the chemotherapy of advanced pancreatic cancer. The GEST study conducted in Japan and Taiwan, China, explored the efficacy of S-1 in the first-line treatment of advanced pancreatic cancer and confirmed that single-agent S-1 was not inferior to single-agent gemcitabine (mOS: 9.1 months vs. 8.8 months) and was well tolerated [12]. Since studies of this drug have only been conducted in Asian populations, its effectiveness needs to be further studied in other populations. (3) Breakthrough in chemotherapy for metastatic pancreatic cancer with the FOLFIRINOX regimen Among fluorouracil-based combination chemotherapy, the fluorouracil, calcium folinate, irinotecan and oxaliplatin (FOLFIRINOX) regimen is the greatest innovation. In the PRODIGE trial, there was a benefit in progression-free survival and overall survival in patients with metastatic pancreatic cancer treated with FOLFIRINOX chemotherapy compared with gemcitabine (mPFS: 6.4 months vs. 3.3 months; mOS: 11.1 months vs. 6.8 months) [13]. However, compared to single-agent gemcitabine, the FOLFIRINOX regimen had a significantly higher incidence of toxic side effects, particularly neutropenia, thrombocytopenia, and diarrhea. During treatment, 37.7% of patients discontinued treatment because they could not tolerate the toxic side effects of the FOLFIRINOX regimen, and 58.3% of patients required dose adjustment [14], so this regimen was limited to patients in good physical condition.The 2015 NCCN guidelines recommended FOLFIRINOX as a neoadjuvant regimen for patients with BRPC. (4) Molecularly targeted drugs Molecularly targeted drugs are the hot spot of research in recent years, and molecularly targeted drugs have the characteristics of high selectivity, less resistance, broad-spectrum effectiveness, and good safety. Recent studies have shown that the combination of anti-VEGF, EGFR-based targeted drugs and gemcitabine has little effect on the improvement of survival in advanced pancreatic cancer. In early studies, only erlotinib resulted in some prolongation of survival, and the 2013 NCCN guidelines recommended the use of erlotinib in combination with gemcitabine for the treatment of advanced pancreatic cancer, but in fact, the benefit of combining erlotinib was very limited at 0.3 months (mOS: 6.2 months vs. 5.9 months) [15]. Recently, the humanized monoclonal antibody nitrozumab has received attention, and the results of a multicenter phase II clinical study showed that nitrozumab in combination with gemcitabine for advanced pancreatic cancer was significantly prolonged compared to gemcitabine alone (mOS: 8.7 months vs. 6.0 months) [16], and its large-scale clinical studies are worthwhile. New targeted therapies are also being tried, and in 2012, ESMO (European Society of Oncology Annual Meeting) reported the use of TH-302, a new targeted agent targeting hypoxic tumor cells, in pancreatic cancer, and in 2015, the final report of this study was published, in which 214 patients with primary locally advanced pancreatic cancer were randomized to gemcitabine alone or in combination with a new targeted agent targeting hypoxic tumor cells TH-302 (340 mg/m2 and 240 mg/m2), and while no significant difference in OS was obtained, the median OS in the combined high/low dose TH-302 group was 8.7 months and 9.2 months, respectively, which was better than the 6.9 months in the single-agent group. This study suggests that there is still more room for research on targeted therapy for pancreatic cancer [17]. 3. Progress in radiotherapy for pancreatic cancer Because of the anatomical characteristics of pancreatic cancer, the adjacent organs have low tolerance to radiotherapy and pancreatic cancer has poor sensitivity to radiotherapy, so the effect of radiotherapy alone is often poor. In recent years, radiotherapy technology has advanced rapidly, and techniques such as three-dimensional conformal radiotherapy and intensity-modulated conformal radiotherapy have emerged, which have significantly improved the accuracy of radiotherapy and reduced radiation damage to surrounding normal tissues [18]. Some studies suggest that radiotherapy can improve the local control rate of patients with intermediate to advanced unresectable pancreatic cancer [19]. According to the characteristics of pancreatic cancer, it is difficult to have a major breakthrough with single radiotherapy, and most studies are currently focusing on combined radiotherapy. (1) Radiotherapy for unresectable pancreatic cancer Current clinical studies suggest that appropriate radiotherapy given after systemic treatment for patients with locally advanced pancreatic cancer can improve survival. In a study by Japanese scholars, for initial unresectable pancreatic cancer, single-agent S-1 oral chemotherapy was given for 4 weeks followed by local radiotherapy with GTV 50Gy/40f and simultaneous oral S-1, and oral single-agent S-1 maintenance after radiotherapy, with mPFS of 6.7 months and mOS of 14.3 months [20]. There is also a study in which mPFS of 9.3 months and mOS of 15.2 months were achieved in unresectable pancreatic cancer treated with concurrent radiotherapy followed by gemcitabine combined with S-1 regimen [21]. (2) Neoadjuvant radiotherapy for pancreatic cancer A systematic review and Meta-analysis of bulk cases showed that: for surgically resectable cases, there was no statistically significant difference in either surgical resection rate or postoperative median survival between preoperative neoadjuvant therapy and postoperative adjuvant therapy; however, for cases assessed as unresectable preoperatively, 1/3 of patients were radically resected after neoadjuvant radiotherapy and achieved a postoperative median survival comparable to that assessed preoperatively (3) Intraoperative pancreatic cancer is a major cause of pancreatic cancer. (3) Intraoperative radiotherapy for pancreatic cancer After resection of pancreatic cancer, there may be unclear tumor margins or local residual tumor, when a high dose of radiotherapy can be administered to the tumor bed and surrounding tissues under direct vision conditions, avoiding normal tissues. It can be used to prevent recurrence in surgically resected pancreatic cancer. Some studies suggest that intraoperative radiotherapy is superior to preoperative radiotherapy for resectable tumors, but there is also literature that suggests that patients with preoperative radiotherapy may benefit more in terms of survival, but all of these studies may have selection bias, so the support of a large sample of randomized controlled studies is needed [23]. Therefore, the 2012 ESMO guidelines define intraoperative radiotherapy for resectable pancreatic cancer as an investigational treatment and do not recommend its routine use. In 2013, the Massachusetts General Hospital reported 194 cases of unresectable pancreatic cancer treated with intraoperative radiotherapy, with survival rates of 49%, 16% and 6% at 1, 2 and 3 years, respectively, and another 6 patients (3%) surviving for more than 5 years [24]. (4) Postoperative radiotherapy for pancreatic cancer Postoperative radiotherapy for pancreatic cancer also has a certain improvement in survival, and some studies have shown that the median survival period was 21.1 months and 15.5 months, the 2-year survival rate was 44.7% and 34.6%, and the 5-year survival rate was 22.3% and 16.1%, respectively, when compared with not receiving postoperative adjuvant radiotherapy. The risk of death was significantly reduced by postoperative radiotherapy compared with no radiotherapy [25]. Most studies now suggest that postoperative radiotherapy combination regimens improve overall survival, while gemcitabine-containing radiotherapy combination regimens improve tumor-free survival, thus recommending gemcitabine-containing chemotherapy in combination with radiotherapy as an adjuvant treatment modality for patients with surgically resected pancreatic cancer. In conclusion, with the advancement of technology, pancreatic cancer surgery and radiotherapy have made great progress, but how to improve disease-free survival is still an important issue to be faced by the medical community.