The study published in the New England Journal German AIO-94 in 2004 laid down the current standard of neoadjuvant treatment for rectal cancer – simultaneous radiotherapy, and it has been more than 10 years since then. This treatment modality has reduced the local recurrence rate of rectal cancer to about 4%, but the proportion of distant metastases is still 20-30%, and how to reduce distant metastases in these patients is the focus of research in recent years. The addition of oxaliplatin sensitization modality Based on the efficacy of oxaliplatin in advanced colorectal cancer and its efficacy in adjuvant chemotherapy for colon cancer, which was first widely studied, five major studies have integrated the use of oxaliplatin as sensitization in neoadjuvant therapy for rectal cancer since 2003, namely ACCORD-12 (N=598) in France, NSABP R-04 (N=1156) in the United States, and STAR-04 (N=1156) in Italy. 1156), STAR-01 (N=747) in Italy, PETTAC-6 (N=1094) in Europe, and CAO/ARO/AIO-04 (N=1274 study) in Germany, which share a similar study design and all add weekly oxaliplatin to standard 5-fluorouracil (5-FU)/capecitabine as co-sensitizer, in terms of short-term efficacy only the AIO-04 study showed an increase in pCR (13% vs 17%), while the other four studies all showed that adding oxaliplatin in this way only increased toxicity but not efficacy, with pCR rates of 14% vs 19%, 19% vs 21%, 16% vs 16%, and 11% vs 13%, respectively. Therefore, experts in Europe and the United States do not see the need for further studies of sensitization modalities. Oxaliplatin full dose addition A very important reason for the high rate of distant metastases is that, according to the current standard of care, patients with locally progressive rectal cancer undergo surgery after 5 weeks of concurrent radiotherapy and 6-8 weeks of rest, and adjuvant chemotherapy is started only about 4 weeks after surgery, then patients will receive systemic therapy 4-5 months after diagnosis, during which time micrometastases have formed. In addition, approximately 20% of patients do not receive adjuvant chemotherapy due to toxicity of preoperative therapy or surgical complications or poor surgical recovery. As a result, there is an increasing number of studies on moving systemic chemotherapy forward to neoadjuvant chemotherapy, including three models: first, adding a full dose of systemic chemotherapy before radiotherapy, second, adding a full dose of chemotherapy during the interval between radiotherapy and surgery, and third, adding a full dose of systemic chemotherapy simultaneously during radiotherapy. Spanish scholars were the first to do a study of the first modality, a phase II study Spanish GCR-3, comparing standard treatment capecitabine combined with radiotherapy followed by TME surgery followed by adjuvant chemotherapy with 4 courses of CAPOX regimen induction followed by concurrent radiotherapy and TME surgery, unfortunately the results of this study were negative with pCR rates of 13% vs 14 Unfortunately, the results of this study were negative, with pCR rates of 13% vs. 14%, 5-year DFS of 62.1% vs. 64.3%, and 5-year OS of 77.9% vs. 74.7% in the two groups, respectively. A small single-arm study with 8 courses of FOLFOX induction followed by concurrent radiotherapy and TME surgery was also reported at ASCO last year, achieving a 33% pCR rate. In contrast, a recent study reported in Lancet Oncology is an attempt at a second modality, a phase II study divided into 4 groups with 0, 2, 4, and 6 courses of mFOLFOX6 regimen of neoadjuvant chemotherapy added during the interval between the end of neoadjuvant radiotherapy and radical TME surgery, showing corresponding pCR rates of 18%, 25%, 30%, and 38, respectively, with a pCR rate of Patients with pCR increased with the number of interval neoadjuvant chemotherapy courses, and the increase in neoadjuvant chemotherapy did not increase the difficulty of surgery or postoperative complications, confirming the feasibility of adding neoadjuvant chemotherapy after neoadjuvant radiotherapy. For the third mode of trial that is the FOWARC study group B, in which the author participated, we studied the effect of 5 courses of FOLFOX synchronized with radiotherapy, and the results showed a significant increase in pCR rate (28% vs. 14%), and this treatment mode is a feasible treatment mode although it increases toxicity but does not decrease compliance. Addition of other drugs In addition to oxaliplatin, the integration of many other drugs is being explored. Studies of cetuximab include the EXPERT-C study, which compared 4 courses of CAPOX followed by concurrent radiotherapy with or without cetuximab, and showed that cetuximab did not increase pCR rates, while another study, S0713, combined cetuximab with weekly CAPOX and continued into the radiotherapy period with reduced intensity to every three weeks, with a pCR rate of 25%, which Neither study showed a role for cetuximab on neoadjuvant, or concurrent radiotherapy, which is different from the increased sensitivity to radiotherapy seen with cetuximab in head and neck tumors, and the mechanisms involved deserve investigation. While bevacizumab integration is also being explored in neoadjuvant therapy, the E3204 study explored the effect of bevacizumab in combination with CAPOX in concurrent radiotherapy, achieving very good long-term outcomes, 5DFS 80%, OS 81%, despite no increase in pCR rates. A similar study is underway with another anti-angiogenic agent, abciximab. In addition, the integration of irinotecan PARP 1/2 inhibitors, temozolomide, and HSP 90 inhibitors has been reported sporadically. Feasibility of chemotherapy alone Studies in the Netherlands have shown that in the TME years, the addition of local radiotherapy only improves local control rates and does not increase overall survival. While the absolute decrease in local recurrence rate was about 10% vs 5%, this 5% decrease in local recurrence came at the cost of an increase in the incidence of post-surgical bowel dysfunction from 30% to 60% and a tendency to worsen rather than remit over time. In contrast, a number of studies have shown that systemic chemotherapy is effective in controlling the primary focus of rectal cancer, suggesting that there may be some chemotherapy-sensitive patients who may not require radiotherapy. Such exploration was carried out in Group C of the FOWARC study in which the author participated. After 4-6 courses of FOLFOX chemotherapy alone, patients with unsatisfactory regression or positive postoperative CRM and more than 4 lymph node metastases received radiotherapy, and only 8 patients out of 165 patients received radiotherapy. A complete remission rate of 6.1% was obtained, with a significant stage reduction rate of 35.8%, suggesting that at least these patients can create a good resection plane for surgery without radiotherapy, although of course the long-term local recurrence remains to be followed up. The larger study on chemotherapy alone is the PROSPECT study designed by the US NCCTG, which will include 1060 studies, and the results of these two studies will hopefully change the current standard of care.