The prevalence of rectal cancer is relatively high. Additionally, there were predictions that the prevalence of rectal cancer may deteriorate , and even tend to among a younger population . Despite decades of exploration, in terms of treatment options, researchers still hold mixed opinions on the efficacy of neoadjuvant therapy that has been widely used. For example, national guidelines in the United States have supported the use of neoadjuvant CRT for all patients with stage Ⅱ-Ⅲ rectal cancer since 2002 . However, many researchers think that this treatment option is no different from upfront surgery in the survival rate of patients .
The main outcome indicators of our analysis were the 5-year OS and DFS. The results demonstrated that neoadjuvant therapy was effective in improving the 5-year OS and DFS of patients, which was consistent with the conclusions of Nagasaki et al.  and Kao et al. . A subgroup analysis was conducted to increase credibility, considering the heterogeneity of the results. In terms of the type of studies, further research showed that both RCTs and OBSs neoadjuvant therapy could improve the long-term OS as well as DFS of patients.
Focusing on neoadjuvant treatment regimens, neoadjuvant CRT was beneficial to improve the 5-year OS and DFS of the patients compared with the control group. Sun et al.  and Kao et al.  had the same conclusions. Interestingly, two RCTs (Wang et al.  and Sprenger et al. ) reached the opposite conclusions using TME. In our study, more OBSs were included, in which patients with lower age, lower tumor location, and better tolerance were more likely to receive neoadjuvant therapy . For example, patients aged over 75 years had a higher risk of complications after radiation exposure and were less likely to receive neoadjuvant CRT in OBSs. However, RCTs eliminated the differences between the groups of patients, which may be one of the reasons why neoadjuvant CRT had no benefit to survival in RCTs. Furthermore, the use of TME may also mask the survival benefits . Therefore, a retrospective study deserved attention. The patients who participated in the study also used TME during surgery, but the conclusions indicated that neoadjuvant therapy could significantly improve the 5-year OS and DFS. Interestingly, the subjects of this study had rectal cancer with lymph node metastasis . Therefore, we postulated that patients with lymph node metastasis were more likely to benefit from neoadjuvant therapy. The effect of neoadjuvant therapy may also be affected by circumferential resection margins (CRM) and extramural vascular invasion (EMVI). Studies have shown that positive CRM would indicate a high risk of recurrence . The EMVI was also considered to be related to poor outcomes . Therefore, subsequent studies may explore these factors to promote more selective and personalized treatment of patients with resectable rectal cancer.
Regarding the use of neoadjuvant SCRT, the results of our study and Folkesson et al.  supported the claim that neoadjuvant SCRT could achieve better long-term survival rates for patients with rectal cancer. Pettersson et al.  proposed that neoadjuvant SCRT could be used to treat patients who were intolerant to neoadjuvant CRT. However, the findings of Sebag-Montefiore et al.  and van Gijn et al.  did not support the above conclusion. The use of TME might be an important factor contributing to this result, which reduced the risk of LR and may make neoadjuvant SCRT less important in reducing the LR . At the same time, TME could reduce CRM involvement and improve the survival rates of patients . Hence, the survival benefits of neoadjuvant SCRT could not be reproduced in the above studies.
On the other hand, our data indicated that the neoadjuvant RT (other than neoadjuvant SCRT) did not bring benefits to the 5-year OS of patients (HR: 0.83, 95% Cl: 0.65–1.02). Neoadjuvant RT may induce metastasis of molecules such as the vascular endothelial growth factor (VEGF) that stimulate angiogenesis, whose over-expression was associated with distant metastasis . The high rate of distant metastasis was also an important factor in the increased mortality of patients receiving neoadjuvant therapy . Additionally, adverse effects caused by neoadjuvant RT (such as anastomotic leakage, thrombocytopenia, leukopenia, poor wound healing and radiation proctitis, etc.) may not only affect the quality of life of patients but also indirectly reduced the life expectancy [14, 66, 67]. Although neoadjuvant RT could benefit long-term DFS (HR: 0.83, 95% Cl: 0.75–0.91), the tumor-killing effect of neoadjuvant RT may be masked by its adverse effects and fail to improve 5-year OS.
The application of neoadjuvant chemotherapy in this study did not increase the long-term survival rate of patients compared with the control group. The impact of a small sample size should be considered. Currently, an RCT (NCT01515787) is exploring whether neoadjuvant chemotherapy could replace neoadjuvant CRT and effectively treat patients with stage Ⅱ-Ⅲ rectal cancer .
Regarding the staging of rectal cancer patients, the study demonstrated that neoadjuvant therapy was effective in improving the 5-year OS and DFS for patients with stage Ⅱ-Ⅲ, which was similar to the indications proposed in the NCCN guidelines .
In terms of tumor location, the data of our study showed that compared with the control group, patients with resectable mid/low rectal cancer had better 5-year OS and DFS after neoadjuvant therapy, whereas the resectable upper rectal cancer showed no benefit in the 5-year OS (HR: 0.95, 95% Cl: 0.87–1.02). The conclusion that neoadjuvant CRT and neoadjuvant SCRT may not be suitable for the treatment of upper rectal cancer was consistent with the views of Tabchouri et al.  and Rades et al. . The possible reason for this is that the location of mid/low rectal cancer was relatively fixed, whereas upper rectal cancer was more active and had poor therapeutic effect. However, the low number of included articles was also a factor that should be considered. There were similar views in the ESMO clinical practice guidelines: If upper rectal cancers located above the peritoneal reflection failed to benefit from neoadjuvant SCRT or neoadjuvant CRT, treating them as colon cancer was recommended .
As far as the included regions were concerned, patients could achieve 5-year OS benefits with the effect of neoadjuvant therapy, and patients in Asia seemed to benefit more. As for 5-year DFS, neoadjuvant therapy could improve the DFS of Asian and European patients to a limited extent, whereas patients in America had no improvement in DFS. Black race was one of the high-risk factors for poor prognosis . Considering that the proportion of blacks in America was higher than in other regions may be a reason why there was no survival benefit for patients in America in our study. There were only two articles from America among the articles included in this subgroup analysis for DFS.
This study had some limitations: First, the OBSs were included in this meta-analysis, so the level of evidence inevitably decreased. Also, the diagnosis of clinical staging has not been standardized, and the preoperative staging methods were diverse. The difference in patient staging caused by preoperative staging methods made it difficult to specifically assess whether the conditions of patients were overestimated or underestimated. Analysis of some related factors affecting the prognosis of rectal cancer patients could not be performed due to lack of data, such as gender and gene type. Some studies suggested that the narrower pelvis of men would affect the prognosis of men with rectal cancer . Also, the gene type of the tumor was an important factor affecting the prognosis of patients . Relevant subgroup analysis was not conducted due to the small number of studies on early rectal cancer. However, it was gratifying that we analyzed the efficacy of various neoadjuvant treatments on different locations and stages of rectal cancer from multiple angles, explored its impact on the long-term survival rate of patients with resectable rectal cancer, and provided new ideas for further research on resectable rectal cancer.