Rectal cancer is one of the most common gastrointestinal malignancies worldwide, with an estimated incidence of 39,670 in the United States in 2010, accounting for the 3rd highest number of gastrointestinal tumors [1]. After more than 200 years of development, the treatment mode of rectal cancer has evolved from the initial purely surgical treatment to today’s multidisciplinary comprehensive treatment mode based on surgical treatment, which includes preoperative neoadjuvant therapy that has made significant breakthroughs in recent years. In China, low-grade rectal cancer (tumor <6 cm from the anal verge) accounts for about 75% of all rectal cancer patients, and is already in the locally progressive stage at the time of diagnosis. In the traditional treatment concept, Miles surgery is the "gold standard" for treating this group of patients, but the permanent artificial anostomy and urogenital dysfunction brought about a lot of difficulties for patients and significantly reduced their quality of life. Neo-adjuvant therapy, which was first proposed in the 1990s, has brought new hope to patients with low-grade rectal cancer. In this paper, we will review the development and current status of neo-adjuvant therapy for low rectal cancer. The development of neo-adjuvant therapy dates back to the first application of the concept of adjuvant radiotherapy in the 1980s, when the concept of total mesorectum excision (TME) was not yet proposed and the local recurrence rate of rectal cancer after surgery was as high as 50% [2], and medical doctors applied postoperative radiotherapy to control the recurrence of locally progressive rectal cancer and achieved good results [3]. good results [3]. However, 10 years later, a small clinical study reported the first application of radiotherapy before surgery and obtained comparable efficacy to postoperative radiotherapy with less toxic side effects, which was the first introduction of the concept of neoadjuvant therapy in the true sense [4]. A European EORTC trial that included 466 patients treated with low-dose, long-course preoperative radiotherapy for rectal cancer showed that preoperative radiotherapy significantly reduced the local recurrence rate compared to those undergoing direct surgery, but did not improve the overall prognosis [5]. A multicenter randomized clinical trial, CR07/C016, showed a significant reduction in local recurrence rates and an increase in 3-year disease-free survival in patients with rectal cancer treated with a short course of preoperative 5-day radiotherapy compared with postoperative radiotherapy, but no significant increase in overall survival time [6]. A recent study from the Netherlands randomized 1861 patients with resectable rectal cancer without distant metastases into the TME-only and preoperative short-course radiotherapy + TME resection groups and showed that preoperative radiotherapy reduced the 10-year postoperative local recurrence rate by nearly 50% and improved the 10-year survival rate in patients with stage III rectal cancer with negative circumferential margins [7]. On the other hand, a hot study focused on whether the combination of neoadjuvant radiotherapy and chemotherapy is superior to preoperative radiotherapy alone, and the French FFCD 9203 clinical trial randomized 733 patients with intermediate to advanced rectal cancer into preoperative radiotherapy and preoperative radiotherapy groups, showing that the preoperative radiotherapy group had a higher rate of complete pathological remission and a lower rate of local recurrence, but the 5-year disease-free survival rate and overall survival and anus preservation rates were not statistically significant. A large German study in 2004 compared the clinical benefit of preoperative combined radiotherapy compared with postoperative radiotherapy and showed that preoperative neoadjuvant radiotherapy significantly reduced local recurrence, although it did not improve the 5-year survival rate, and patients had significantly lower toxic side effects to radiotherapy [9]. Therefore, neoadjuvant treatment for rectal cancer has undergone three stages of development: postoperative radiotherapy, preoperative radiotherapy, and preoperative combined radiotherapy and chemotherapy, and nowadays combined radiotherapy has become the recognized preferred neoadjuvant treatment option. Neoadjuvant radiotherapy has many advantages compared with postoperative adjuvant therapy: 1.Preoperative patients have better physical condition, high tolerance and light toxic reaction. 2.The blood supply and lymphatic vessels of tumor lesions are not damaged before surgery, so the local concentration of chemotherapeutic drugs in tumor is high and the killing effect on tumor cells is stronger. 3.Control the microscopic cancer and subclinical foci existing before surgery, inhibit the proliferation stimulation of tumor due to surgery. 4.Reduce the primary lesions and clinical stage, and some tumors can even achieve pathologic complete response (pCR), thus increasing the rate of radical resection and anal preservation of low rectal cancer. 5.Improve the effect of radiotherapy and reduce complications. After surgery, the tumor is wrapped by fibrotic scar and the tissues are in a relatively hypoxic state, and the radiosensitivity is reduced. Secondly, part of the small intestine may fall into the pelvic cavity and be fixed by adhesions after surgery, and radiotherapy after surgery is prone to radiation enteritis, while the small intestine did not enter the pelvic cavity before surgery and has good mobility, which is not easily damaged by radiotherapy. Therefore, neoadjuvant radiotherapy can avoid tissue hypoxia caused by surgery, improve the sensitivity of tumor tissues to radiotherapy, and will not lead to radiation enteritis or even intestinal fistula due to the adhesion of small intestine in the pelvis after surgery.6. Through preoperative imaging staging and pathological examination of surgically resected specimens, the sensitivity of tumor cells to chemotherapeutic drugs can be judged, which can guide the selection of chemotherapeutic drugs after surgery and realize individualized treatment. According to the 2010 edition of the National Comprehensive Cancer Network (NCCN, www.nccn.org) guidelines, the Clinical Practice Guidelines for Rectal Cancer (China version) 2010, 1st edition, which was launched in the context of China's national situation, clearly states that for most patients with stage II (lymph node negative, tumor penetrating the muscle layer of the intestinal wall) and stage III (lymph node positive, no distant metastasis) neoadjuvant radiotherapy or neoadjuvant radiotherapy is recommended for most patients with stage II (lymph node negative, tumor penetrating the muscle layer of the intestinal wall) and stage III (lymph node positive, no distant metastasis) rectal cancer. However, neoadjuvant chemotherapy alone is generally not recommended. The American Society Colon& Rectal Surgeons (ASCRS) treatment guidelines also recommend neoadjuvant chemotherapy plus pelvic radiotherapy for stage II and III rectal cancer based on evidence-based medical level 1 evidence. Neoadjuvant radiotherapy Currently, neoadjuvant radiotherapy should reach the sacral headland above and the anal verge below, including perirectal, presacral, internal iliac vessels and lymph nodes, and the following two regimens are mostly used: (1) long course radiotherapy: daily dose of 1.8-2 Gy for 5 weeks, total dose of 45-50 Gy, and surgery 4-8 weeks after the end of radiotherapy. and some European countries. (2) Short course radiotherapy: 5 Gy daily for 5 days, total dose of 25 Gy, surgery after 1 week, mostly used in Sweden and the Netherlands. Both regimens have their advantages and disadvantages. The total dose of long course radiotherapy is larger, but the fractionated dose is smaller, and the toxic side effects are mild. Since tumor necrosis and fibrosis are most obvious only 4-8 weeks after long course of radiotherapy, tumor shrinkage and stage reduction can be reflected, so this is generally recommended as a better time for surgical intervention. However, patients who are not sensitive to preoperative neoadjuvant radiotherapy undoubtedly delay the timing of surgery and tumor progression is not effectively controlled, which affects the long-term prognosis [10]. Short-dose radiotherapy with small total dose and large fractionated dose, short treatment course, good patient compliance, can control postoperative local recurrence, but it is difficult to achieve tumor downgrading and downstaging, and does not help much to improve radical resection and anus preservation rate, and has a higher risk of neuroradiological injury and surgical complications, such as acute lumbosacral plexus injury, postoperative perineal wound infection, and delayed intestinal obstruction [10-12]. At present, there is no definite conclusion on the advantages and disadvantages of the above-mentioned regimens, and the search for accurate indicators to predict the sensitivity of neoadjuvant radiotherapy will be a hot spot for future research. 2.Neoadjuvant radiotherapy Preoperative radiotherapy alone is not meaningful for controlling systemic tumor dissemination, so preoperative combination of systemic chemotherapy is used to make up for this limitation. Neoadjuvant chemotherapy regimens are emerging, and the traditional regimens are mostly 5-Fu-based chemotherapy alone. chemotherapy regimens. The advent of the 3rd generation 5-Fu drug Xeloda (capecitabine, Xeloda) has provided more options for neoadjuvant chemotherapy for rectal cancer. Xeloda is an oral fluoropyrimidine carbamate that converts it to 5-Fu, which is active against tumors, through thymidine phosphorylase (TP), which is found in much higher levels in tumor tissue cells than in normal cells, so that the concentration of Xeloda is five times higher in colorectal cancer tissues than in adjacent tissues, thereby improving the utilization of chemotherapy drugs. In addition, some studies have confirmed that radiotherapy can upregulate the expression of thymidine phosphorylase in tumor cells, so there is a synergistic effect between radiotherapy and Herodar. Oral capecitabine is considered to be comparable to 5-Fu infusion chemotherapy and significantly reduces complications associated with intravenous chemotherapy, and is expected to fully replace 5-Fu in the future [13, 14]. Oxaliplatin is a novel platinum-based anticancer drug that exhibits stronger antitumor activity than conventional carboplatin and cisplatin in the treatment of colorectal cancer and also has radiotherapy sensitizing properties. One study reported that its combination with fluorouracil/formyltetrahydrofolate (5-Fu/LV) or capecitabine for neoadjuvant radiotherapy of rectal cancer achieved a high pathological remission rate (pCR) [15-17]. Another phase I clinical trial confirmed that the combination of oxaliplatin and topoderm in patients with stage T3 rectal cancer was effective in improving anus preservation and reducing postoperative recurrence [18], whereas topoderm alone did not benefit patients [19]. Irinotecan, a semisynthetic derivative of camptothecin, specifically binds to topoisomerase I and causes DNA double-strand breaks, which is currently considered to be a first-line drug for the treatment of metastatic colorectal cancer or a second-line treatment for failed 5-Fu chemotherapy because of its strong radiosensitizing effect in combination with conventional drugs that do not increase the efficacy and may cause toxic side effects [20]. One study used a neoadjuvant chemotherapy regimen of irinotecan + 5-Fu to achieve a pCR rate of 22% and initially showed inhibition of distant metastases [21]. In addition, novel targeted therapeutics including vascular endothelial growth factor (VEGF) receptor inhibitors (bevacizumab) and epidermal growth factor receptor (EGFR) inhibitors (cetuximab) have been shown to consistently inhibit tumor neovascular growth and metastasis and have been approved by the US Food and Drug Administration (FDA) for clinical use. Bevacizumab in combination with 5-Fu or capecitabine has been shown to achieve satisfactory pCR rates [22, 23], and cetuximab has shown good efficacy in patients with rectal cancer carrying the wild-type K-ras gene [24-26]. More large-scale clinical trials are needed to further validate the role of the above drugs in neoadjuvant therapy. A large number of studies have shown that preoperative neoadjuvant radiotherapy can improve the rate of anal preservation and reduce the rate of postoperative local recurrence, but it is controversial whether it can improve overall survival.Machiels et al [27] reported that the radical resection rate of a group of patients after neoadjuvant radiotherapy could reach 60%-89%.Sauer et al [9] compared preoperative radiotherapy + postoperative chemotherapy with postoperative radiotherapy for rectal cancer, and the 5-year local recurrence rate was higher than that of postoperative radiotherapy. The 5-year local recurrence rates were 6% and 13%, respectively, which were statistically different, while the 5-year survival rates were 76% and 74%, respectively, which were not significantly different. A Meta-analysis including 14 randomized controlled clinical studies showed that preoperative adjuvant radiotherapy reduced cancer-related mortality, local recurrence rates, and improved 5-year survival [28]. However, some studies have also concluded that patients with stage II rectal cancer with low-risk recurrence factors do not benefit from neoadjuvant therapy [29]. The NSABP R-03 study from the United States showed that preoperative neoadjuvant radiotherapy only differed from postoperative adjuvant radiotherapy in terms of 5-year disease-free survival, but did not prolong 5-year survival, reduce the rate of local recurrence or increase the chance of sphincter preservation [30]. However, this study did not standardize the surgical approach. weiser et al [31] performed preoperative chemotherapy + long course radiotherapy in 148 cases of low rectal cancer 6 cm from the anus and found that neoadjuvant treatment significantly increased the rate of sphincter preservation. In contrast, although preoperative short-course radiotherapy could control local recurrence, it could not achieve similar effects as long-course radiotherapy in terms of tumor reduction volume, stage reduction, and anal sphincter preservation [9, 32]. In addition, the application of laparoscopic techniques for resection of neoadjuvant treated low rectal cancer can achieve the same overall outcome as open surgery [33, 34]. V. CONCLUSION There is no doubt that neoadjuvant therapy adds new options and hope to the treatment strategy for low-grade rectal cancer, and its therapeutic results are encouraging. Patients with locally progressive rectal cancer can generally benefit from preoperative neoadjuvant radiotherapy, but in clinical practice, taking into account China's national conditions, individualized treatment plans must be formulated by taking into account various factors such as patients' physical conditions, tumor site, size, preoperative stage, developmental speed, and pathological characteristics. On the other hand, basic and clinical studies related to neoadjuvant therapy are still continuing, and several important large sample randomized controlled trials include EORTC (comparison of the efficacy of capecitabine alone and capecitabine in combination with oxaliplatin), NSABP R-04 (comparison of the efficacy of 5-Fu, capecitabine and oxaliplatin alone or in combination), Stockholm III (study of short-course chemotherapy and time to surgery) are underway; preliminary validation has been performed on indicators related to the prediction of neoadjuvant therapy sensitivity in rectal cancer, such as P21 and P53 genes, apoptosis pathway-related proteins, and EGFR. The above findings and the subsequent in-depth studies are expected to provide a series of answers to the hot and difficult questions in neoadjuvant treatment of rectal cancer, and are expected to lead a new chapter in the comprehensive treatment of rectal cancer!