Our findings suggest that the pre-CRT NLR may be a predictor of prognosis in patients with locally advanced lower rectal cancer after nCRT. The NLR reflects the balance of host immunity between pro- and anti-tumor activities. A high circulating neutrophil count is considered to have pro-tumor properties because inflammatory cytokines released from neutrophils induce angiogenesis and promote tumor growth .
Various cutoff values have been used to define elevated NLR in previous studies. Although some studies used cutoff values calculated by statistical methods, the reported NLR cutoff values on patients with rectal cancer who underwent nCRT are inconsistent [27–30]. In this study, a cut-off value of 3.20 for the pre-CRT NLR was significantly related to RFS. Although the pre-CRT NLR score, operation time, and ypT were significantly associated with RFS in the univariate analyses, multivariate Cox proportional hazard regression analysis showed that the pre-CRT NLR was independently associated with RFS. This demonstrates that a pre-CRT NLR greater than 3.20 is a predictor of poor prognosis. “High NLR” suggests a pro-tumor status and a higher possibility of poor radiation response, while “Low NLR” suggests an anti-tumor status and a higher possibility of a positive tumor response and survival  [21, 31] . Chiang et al. showed that preoperative NLR > 3 was associated with a larger tumor size, elevated CEA, and an increased risk of cancer progression and decreased survival in a retrospective analysis including 3,857 patients with stage I to III CRC; interestingly, no significant associations were found in the rectal cancer subgroup . In this study, although all patients with advanced lower rectal cancer underwent nCRT, the group with pre-CRT NLR ≥ 3.20 showed a lower 5-year RFS than the group with pre-CRT NLR < 3.20. This association might be the reason why, as we previously reported, a significant difference was observed in the estimated 3-year local recurrence rate between the group who underwent nCRT and the surgery only group .
To our knowledge, one critical component of the tumor microenvironment is the immune system, and it has become increasingly evident that the immune system plays an integral role in preventing and promoting the development of cancer . Lymphocytes, especially CD4 + or CD8 + T cells and B cells, are thought to play a key role in antitumor host immunity by inducing tumor cell apoptosis . A number of immune cells, in addition to lymphocytes, can directly and indirectly kill cancer cells. In fact, immune cells patrol the body, monitoring all altered cells that become cancerous in a process known as “immunosurveillance.” Through immunosurveillance, the body can effectively recognize and eliminate cancerous cells prior to them causing harm. It is already widely known that lymphocytes play an important role in anticancer activity. Patients with a low NLR have more lymphocytes relative to neutrophils in their blood than patients with a high NLR. This may alter the effectiveness of anti-cancer effects, which ultimately resulted in better RFS in the “High NLR” group of this study (Fig. 3).
In this study, we calculated post-CRT NLR in addition to pre-CRT NLR and examined whether it could be a recurrence risk factor by comparing the pre- and post-before and post-CRT NLR (Table 3). According to the results, distant recurrence tended to occur more frequently in the “High NLR-up” group. In addition, distant recurrence tended to occur more often in the “Low NLR-up" group, which means that the post-CRT NLR was higher than pre-CRT NLR. This may suggest that lower proportions of lymphocytes that make up NLR may be a risk of distant recurrence because of reduced “immunosurveillance.”
The setting of the cutoff value by the ROC curve in medical treatment is used to determine how much sensitivity should be pursued for the benefit of the patient; however, there is no rule as to what point should be pursued. It is important to constantly re-evaluate the interpretation of the numerical values, taking into consideration the purpose of utilization, the characteristics of the target population, the degree of progression of the stage, and the effects of the development of therapeutic means. Information that can be easily obtained from blood tests is important for advanced rectal cancer, where multidisciplinary treatment is becoming mainstream. The NLR can be measured at any facility at a low cost and can be measured frequently in daily medical care. It has a utility value not found in markers and is considered to have great clinical applicability.
In this study, we used the NLR to evaluate the prognosis of local advanced rectal cancer after nCRT; however, in recent years, several other reports have evaluated it using the plate-to-lymphocyte ratio (PLR)   and the monocyte-to-lymphocyte ratio (MLR)  . There is no consensus on which ratio is best to use, including the NLR, and it is hoped that more clinically applicable and simple biomarkers will be discovered.
A limitation of this study is that the sample size was small and provided insufficient data to draw confirmative results, due to the retrospective study design. A future well-controlled, large-scale prospective study is needed to further validate the study findings.