The effective treatment of gastrointestinal tumors has been mainly surgical resection, and all treatments other than surgery are called adjuvant therapy. Neoadjuvant therapy refers to the treatment measures given before surgical treatment, mainly including chemotherapy and radiotherapy. Although the technical level of surgical treatment has developed considerably after more than a century of efforts, such as extensive lymph node dissection and extended radical treatment by combined multi-organ resection, which have improved the prognosis of progressive gastrointestinal tumors, the results of these radical resections are still unsatisfactory. For example, in the current radical resection of rectal cancer, total mesorectal excision (TME) technique has been widely used or routinely applied, and its postoperative local recurrence rate has been reduced to less than 10%, but the 5-year survival rate still hovers around 50% [1-3]. These results suggest that it is difficult to achieve greater breakthroughs in gastrointestinal tumors by surgical treatment alone in a short period of time, and satisfactory results cannot be achieved yet. As early as 1982, Frei [4] first proposed the concept of neoadjuvant chemotherapy, which was also called anterior chemotherapy at that time. Since then, neoadjuvant therapy has received more and more attention and has become one of the important methods to improve patients’ prognosis in recent years. The theoretical basis of neoadjuvant therapy The theoretical basis of neoadjuvant therapy is: 1. control and reduce the primary foci Preoperative radiotherapy can reduce the tumor load to varying degrees and make the tumor down-staging, which is conducive to radical surgical resection. 2. reduce local recurrence and distant metastasis Postoperative residual lesions may accelerate proliferation due to surgical stimulation, and neoadjuvant therapy can inhibit such stimulated proliferation. Neoadjuvant therapy can inhibit this stimulated proliferation, thus suppressing the value-added of tumor and reducing the rate of local recurrence; neoadjuvant therapy can reduce the vitality of tumor cells, which is less likely to be disseminated intraoperatively, and reduce the chance of residual tumor in vivo to metastasize easily after surgery due to the strengthening of blood coagulation mechanism and immunosuppression. 3. Therefore, postoperative radiotherapy may not reach the effective sensitivity and effective blood concentration at the residual lesions. Therefore, neoadjuvant therapy, as the first blow to tumor cells, can play a multiplier effect in the comprehensive treatment of tumor.4. Preoperative radiotherapy thickens the fibrosis of the presacral fascia, reduces the surgical risk of intraoperative presacral vein bleeding and increases the surgical resection rate and radicality.5. Because the small intestine falls into the pelvis after surgery, preoperative radiotherapy can reduce radioactive small intestine injury, reduce radioactive enteritis and reduce postoperative complications such as anastomotic stenosis.6. 6. Through the changes of tumor staging before and after surgery and pathological changes of resected tumor specimens, we can understand the sensitivity of tumor to chemotherapy and radiotherapy, which is beneficial to the selection of appropriate treatment plan and evaluation of prognosis after surgery. In the past, due to the obvious or even strong side effects of chemotherapy drugs, both doctors and patients were not widely used in preoperative chemotherapy for fear of side effects. In recent years, the application of new anti-cancer drugs, especially molecular targeted drugs, has significantly reduced the toxic side effects of chemotherapy, and the fear of chemotherapy has tended to be treated and handled rationally. In 1989, Wikle et al. reported for the first time that the EAP regimen (etoposide, adriamycin and cisplatin) was administered to 34 cases of unresectable progressive gastric cancer treated with chemotherapy at autopsy, and 33 of them were successfully resected with R0 and R1 surgery, which brought a new light to resect unresectable tumors after downstaging. Subsequently, neoadjuvant therapy has received more attention and is increasingly used in clinical practice, and some of them have achieved remarkable efficacy. In principle, neoadjuvant chemotherapy for gastrointestinal tumors adopts multi-drug regimens, and single-drug regimens are basically no longer used. The drugs used are mostly 5-fluorouracil (5-FU), which is degraded to FdUMP after entering the body, and then combined with TS (thymidine nucleoside synthase) with the participation of reduced folic acid to form a stable ternary complex, thus preventing DNA synthesis and leading to cell death. Experimental studies both in vitro and in vivo have shown that the killing effect of 5-FU on tumor cells is significantly enhanced after administration of calcium folinic acid (leucovorin, LV) supplementation. Adjuvant chemotherapy for colorectal cancer has made many new advances in recent years and has undergone 5-FU alone, 5-FU/Lev (levamisole, leucovorin) regimen, 5-FU/LV regimen, 5-FU/LV + OXA (oxaliplatin, oxaliplatin), i.e. FOLFOX, and other regimens. The available studies have shown that the 5-FU/LV regimen is superior to the 5-FU/Lev regimen. The results of a recent multicenter, large-sample MOSAIC trial showed that the FOLFOX regimen was superior to the 5-FU/LV regimen. Oxaliplatin and Kepitol (CPT-11, irinotecan) are often used in combination with 5-FU in neoadjuvant chemotherapy for the treatment of liver metastases from colorectal cancer. Pozzo et al [8] applied Kepitol + 5-FU/LV (FOFIRI regimen) chemotherapy for 12 weeks (6 cycles) in 40 patients with liver metastases from colorectal cancer that could not be surgically resected, and 13 cases were converted to resectable and Bismuth et al [9] treated 330 patients with unresectable liver metastases from colorectal cancer with OXA + 5-Fu/LV (FOLFOX regimen), 53 were converted to resectable, with survival rates of 54% and 40% at 3 and 5 years postoperatively, but tumor recurrence was also observed in 64% of patients. Neoadjuvant chemotherapy is mostly referred to the same regimen as adjuvant chemotherapy or combined with the application of radiotherapy on top of it. The neoadjuvant regimen for colorectal cancer is relatively uniform, and the application of neoadjuvant therapy has achieved more satisfactory results in terms of tumor downgrading, increasing the rate of anal preservation, reducing local recurrence, and increasing the resection rate of liver metastases. 5-FU/LV regimen can still be used as the first-line drug, but various data have confirmed the superiority of FOLFOX regimen. Currently, the FOLFOX4 regimen is used as the first-line drug and the FOFIRI regimen as the second-line drug; or the FOLFOX4 regimen is used as the second-line drug when the FOFIRI regimen is used as the first-line drug. Most neoadjuvant treatment for patients with rectal cancer is performed with the above regimen plus radiotherapy. Osti et al. treated 140 patients with stage T2 and T3 rectal cancer with the Mayo Clinic regimen of 5-FU (0.35/m2)/LV (10 mg/ m2) on days 1-5, along with radiotherapy of 1.8 Gy 5 days a week for 25 sessions totaling 45 Gy, and all were surgically resected after an interval of 4-6 weeks. In 34 cases, the postoperative samples were negative and tumor-free, 45 cases were T1 stage, 31 cases were T2 stage, and 32 cases were T3 stage; the 5-year survival rate was 71.3%, among which the recurrence-free survival rate was 79.4%. The combination of 5-FU plus one or two of adriamycin (ADM), mitomycin (MMC), nitrosoureas or platinum-based agents is mostly advocated for the treatment of gastric cancer. ) plus 5-FU chemotherapy, 68.2% of the patients underwent total gastrectomy with expanded lymph node dissection and survived for a mean of 14 months after surgery, while the control group without neoadjuvant chemotherapy survived only 4 to 6 months. A British study showed that more than 500 patients with gastric cancer treated with preoperative chemotherapy with ECF (epirubicin, 5-FU and cisplatin) led to downstaging of the tumor and improved surgical resection and tumor-free survival rates, but overall survival was unchanged. In contrast, Hartgrink et al. applied preoperative chemotherapy with FAMTX (5-FU, doxorubicin and methotrexate) to 29 of 59 patients with gastric cancer, and the mean survival time was 18 months at 83 months postoperatively, compared with 30 months in the surgery-only group (p=0.17), which did not show the superiority of preoperative chemotherapy with the FAMTX regimen. The superiority of preoperative chemotherapy with FAMTX regimen was not demonstrated. So far, the application of neoadjuvant chemotherapy in gastric cancer is not as widespread as in colorectal cancer, and there is not yet a standard neoadjuvant treatment plan, and the ideal plan needs to be further explored in many aspects. 3.The dosing cycle of neoadjuvant chemotherapy drugs There is no fixed dosing cycle for neoadjuvant therapy. Generally, radiotherapy alone or radiotherapy plus chemotherapy is given 5 times a week at 1.8~2.0Gy each time, which takes 4~5 weeks to reach 40~45Gy, and then 4~6 weeks after surgery. However, there is no fixed cycle of preoperative chemotherapy alone. Usually, physicians and patients are often concerned about only one cycle of chemotherapy due to side effects such as increased myelosuppression due to the long duration of chemotherapy, or concern about delaying the timing of surgery. There are also patients who do not want to undergo surgery because of the better results of neoadjuvant chemotherapy and prolong the duration of preoperative chemotherapy. Recently, a study showed that after 2 cycles of effective neoadjuvant chemotherapy, the histological necrosis of tumor changes significantly, while more than 3 cycles, the tumor shrinkage is not obvious, and more than 4 cycles, the tumor has a tendency to increase. 4.Administration route of neoadjuvant chemotherapy 1.Intravenous continuous drip is better than intravenous push When 5-FU/LV regimen was accepted as the standard regimen of chemotherapy for colorectal cancer, it mostly followed the intravenous push adopted by Mayo Clinic, the developer of the regimen. However, it was later found that the plasma half-life of 5-FU was only 8-14 minutes, and the effective blood concentration was maintained for a shorter period of time when intravenous push was administered, thus the use of continuous intravenous infusion could improve the antimetabolic effect of 5-FU in the S phase with fewer side effects. LV100~200mg/m2 intravenously for 2 hours and 5-FU40~0600mg/m2 intravenously for 22 hours, applied for 2 days every 14 days; the intravenous push group (FUFOL) LV100200mg/m2, and 5-FU400mg/m2 intravenously for 15 minutes, applied for 5 days every 28 days. The results showed that during the treatment period of 24 to 36 weeks, the total amount of drugs used in the LV5FU2 group was higher than that in the FUFOL group, but its grade III-IV toxic reactions were lower than those in the FUFOL group, 10% and 26%, respectively, with significant differences. 2.Regional arterial chemotherapy Transregional arterial chemotherapy can increase the blood concentration in target organs, reduce systemic toxic effects and improve patient tolerance, thus increasing the resection rate of liver metastases and the radical and anus-preserving rate of low rectal cancer. The main methods are trans-femoral intervention with hepatic artery drip (HAI) chemotherapy for colorectal cancer liver metastases and trans-superior rectal artery intervention for rectal cancer. However, the effect of HAI has not been affirmed. Recently, De Jong et al. summarized the treatment of colorectal cancer liver metastases with Kepto via HAI, and compared with intravenous application, unfortunately, no practical application was found. Since the application of 5-FU, people have been searching for a variety that can be taken orally, in order to achieve the ideal requirements of convenient oral administration, good patient compliance, high efficacy, no destruction by digestive juices and light toxic side effects. In the past, there were many kinds of drugs, such as 5-FU, fluorescine (FT-207), ufluazide (UFT), and fluorouracil (FUDR), but they were not satisfactory. Capecitabine is a 5-FU precursor drug, which is converted into 5-FU by TP (thymidine phosphorylase) after oral administration. TP has a high concentration in tumor cells but very little in normal cells, so it has a targeted effect, high anti-tumor activity and low side effects. Radiotherapy can also enhance the activity of TP, thus enhancing the therapeutic effect of capecitabine. Kim et al. used capecitabine + LV combination radiotherapy preoperatively in 45 patients with T3/T4Nx, and 63% of them were down-staged, and 37 of them underwent radical surgery. After neoadjuvant chemotherapy with capecitabine in 30 patients with T3 and T4 low-grade rectal cancer, Yu et al. achieved better stage-reducing results and all 30 cases underwent radical surgical resection. The postoperative pathological TNM stage showed that there were 8 cases of T0 stage (tumor-free), 5 cases of T2N0 stage, 9 cases of T3N0 stage, and 8 cases of T2~3N1 stage, among which 26.67% of cases had complete disappearance of tumor. 5. Problems and Prospects Neoadjuvant chemotherapy for gastrointestinal tumors has not been widely used in clinical practice. At present, it is mainly applied to patients whose tumors are difficult to be resected surgically or have distant metastases, or to those whose tumors are reduced to facilitate the preservation of the anus. Neoadjuvant chemotherapy for gastrointestinal tumors has positive effects and can improve the resection rate of liver metastases from gastrointestinal tumors and the success rate of radical resection and anus preservation for low stage T3 and T4 rectal cancer. However, neoadjuvant therapy itself still has many problems to be solved, including: 1. in some cases, the disease progresses after neoadjuvant chemotherapy is applied, which delays the surgical treatment; 2. the effective tumor reduction by treatment may make the scope of intraoperative resection difficult to determine, and patients may refuse surgery or continue radiotherapy because of the good results; 3. there is a lack of strict pre-treatment tumor staging and surgical resection and lymph node dissection criteria; radiotherapy makes the peri-tumor resection and lymph node dissection difficult; and radiotherapy makes the peri-tumor resection difficult to determine. The lack of strict pre-treatment tumor staging and surgical resection and lymph node dissection standards; the thickening of peritumor tissues and inflammatory cell infiltration caused by radiotherapy make it difficult to accurately determine tumor staging by preoperative imaging, which do not facilitate accurate evaluation of neoadjuvant treatment effect. In conclusion, neoadjuvant therapy for gastrointestinal tract tumors has achieved encouraging clinical results, but there are still some problems that need to be studied in further depth and detail, especially randomized prospective studies on large samples of gastric cancer cases.