Colorectal cancer (CRC) is still a major cause of cancer-related death worldwide [
1]. In contrast to the USA, in which the age-standardized incidence and mortality rates of the disease have decreased noticeably in recent years, the incidence rate is still increasing in China [
2]. Although the majority of early stage cases can be cured by surgery or surgery plus adjuvant chemotherapy (AC) [
3], over a third of patients will die within 5 years [
4]. Developing for a reliable and easily accessible prognostic indicator is still important in practice, particularly for the determination of therapeutic strategies.
Cancer-associated inflammation is regarded as one of the hallmarks of cancer [
5] and plays an essential role at different stages of cancer development [
6]. The elevated cytokines and chemokines in the inflammatory environment can alter not only the proportions of inflammatory cells [
7,
8] but also their functions [
9]. Lymphocytes are an important component of leukocytes and are the main player in adaptive anticancer immunity [
10]. Lymphocytes have profound effects in many aspects of cancer, such as inhibiting their occurrence [
11], preventing dissemination [
12] or recurrence [
13], and regulating treatment response [
14]. Not unexpectedly, the count of these cells in peripheral blood as well as in the tumor microenvironment (TME) was also found to have an important role in prognosis in many malignancies [
15‐
17] including CRC [
18‐
20]. Taking into consideration that the altered proportion of leukocytes in the inflammatory environment would also be meaningful in reflecting the anticancer immune response, a series of new prognostic indicators were established to further improve the prognostic efficacy based on absolute lymphocyte count (LC) in CRC, including the neutrophil to lymphocyte ratio (NLR: defined as the absolute number of neutrophils divided by the number of lymphocytes) [
21], lymphocyte to monocyte ratio (LMR: defined as the absolute number of lymphocytes divided by the number of monocytes) [
22], and LANR (defined as the absolute number of lymphocytes multiplied by the level of albumin and divided by the absolute number of neutrophils) [
23].
Interestingly, some inflammation-related proteins were also found to be prognostically meaningful in addition to these inflammatory cells. Fibrinogen (FIB), which is a glycoprotein that is mainly synthesized by the liver as an acute-phase response, was previously thought to play a role mainly in coagulation [
24]. However, it was found that FIB could also be released by cancer cells [
25] and involved in many other biological processes including tumor angiogenesis, cancer cell proliferation, adhesion, and migration [
26,
27]. Based on these data, mounting evidence indicates that a frequently elevated FIB in cancer patients is associated with poor survival [
28‐
33] which includes CRC [
34,
35]. Nonetheless, it is worth noting that neither single LC nor single FIB was sufficient to provide a precise prediction of the prognosis in CRC. As previous studies have indicated, the area under the curves (AUCs) for individual LC in predicting the outcome ranged from 0.58 to 0.61 with a relatively low sensitivity or specificity [
19,
36]. In line with this, the AUC for FIB in predicting overall survival (OS) was only 0.57 [
37], and the optimal cutoff points were highly inconsistent in these studies for both LC and FIB [
19,
34,
38]. Therefore, it is plausible that a combination of these two indicators, namely, the LC to FIB ratio (LFR) could be more reliable in prognosis for CRC patients. However, there is currently little research on the LFR in CRC.
In this study, we aimed to explore the prognostic value of LFR and compare its prognostic efficacy with individual LC and FIB. Further, we tested the usefulness of LFR in normal carcinoembryonic antigen (CEA) cases in CRC.
Discussion
In this study, we found that the LFR could be used as a reliable prognostic indicator in nonmetastatic CRC, and its prognostic efficacy is likely to be superior to individual LC or FIB with regard to OS. Patients with a relatively low LFR had worse survival than those with a high LFR, and the LFR was an independent risk factor for the outcome in these patients. Additionally, the role of LFR in prognosis was maintained in CEA normal cases and could be effectively distinguished from those that have a poor outcome. To the best of our knowledge, this is the first report concerning the role of LFR in CRC.
It is notable that the prognostic value of LC and FIB has been validated in CRC previously but with individual limitations. For LC, Liang et al. collected 1332 stage 2 patients which included 459 patients who presented high risk of AC, and their results showed that pretreatment LC (cutoff 1300/mm
3) was independently associated with survival [
24]. In line with this, Noh et al. performed a study with 231 stages 2–3 patients who received curative surgery in addition to the subsequent FOLFOX regimen AC and suggested that LC was also independently correlated with the outcome [
18]. However, the use of LC in predicting survival may limited by its relatively small AUC and inconsistent cutoff points. For example, Iseki et al. reported that the AUC for a single LC (cutoff 1700/mm
3) in predicting DFS was 0.55, which was not statistically significant, but it was useful in predicting OS (cutoff 1100/mm
3,
AUC = 0.59) [
19]. Similarly, Tanio et al. found that the AUC for a single LC (cutoff 1460/mm
3) in predicting OS was only 0.55 [
43]. For FIB, Silvestris et al. conducted a study with 139 metastatic cases that received bevacizumab-based therapy and found that the AUC for FIB in forecasting DFS was 0.62 and further reduced to 0.57 in predicting OS [
37]. However, similar to single LC, the cutoff points for FIB were highly inconsistent as described by a systematic review and meta-analysis [
34]. In recent years, some new prognostic indicators have been established based on these markers in CRC to improve prognostic efficacy. Examples have been reported, such as NLR [
21], LMR [
44], the FIB and NLR ratio [
45], and the FIB to prealbumin ratio [
41,
42]. However, it is notable that reports regarding the role of LFR in cancer are still scarce, with only a few relevant studies but only with some relevant studies. For example, Liu et al. included 375 stages 1–4 non-small cell lung cancer patients and explored the prognostic role of the FIB-to-lymphocyte percentage ratio (FLpR), and the results indicated that patients with a high FLpR would have an increased risk of death [
46]. In addition, Huang et al. indicated that a high FIB to LC ratio (FLR) correlated with peritoneal dissemination in gastric cancer [
47]. Though these results are not from CRC, they could also support the idea that a low LFR (equal to a high FLpR or FLR) correlates with poor outcome. Interestingly, we also found a positive correlation of FLR with LMR and PNI but a negative correlation with NLR and PLR. As the prognostic role of these markers has been extensively validated in previous reports [
21,
41,
43], we believe it could partly validate the value of LFR in our study.
Mechanistically, it is well established that lymphocytes have an extensive effect in cancer, including the inhibition of occurrence and growth [
11,
48], prevention of dissemination [
12], and recurrence [
13]. In recent years, colorectal cancer stem cells (CCSCs) or cancer-initiating cells have been identified and are thought to be the ultimate source of cancer initiation, progression, resurrection, and treatment resistance [
49‐
51]. These cells in the circulatory system play a key role in cancer metastasis and recurrence [
52,
53]. Interestingly, lymphocytes can efficiently recognize and eradicate these cells [
54]. In addition, FIB has been found to have a broad effect on cancer development except for the aforementioned involvement of biological processes [
27,
28]. Recently, it has also been reported that FIB in the TME can contribute to the invasiveness of glioblastoma tumor-initiating cells [
55], and it can promote malignant biological tumor behavior by regulating epithelial-mesenchymal transition [
56]. As in CRC, other researchers have found that FIB can coordinate with platelets in protecting cancer cells from natural killer cytotoxicity [
57] and support tumor growth as well as local invasion and metastasis [
58]. These functions could contribute to the support of CCSCs. Additionally, cancer-related inflammation is regarded as a hallmark of the disease [
5], and some inflammatory factors can have a profound role in the development of the disease, particularly IL-6. As previous studies have indicated, peripheral blood IL-6 is significantly elevated in CRC patients [
59,
60], which could contribute to T-lymphocyte cell-mediated immunosuppression [
61]. As indicated in another study conducted in lung cancer, patients with high circulating IL-6 levels have significantly more T-regulatory cells and increased programmed cell death protein-1 expression on lymphocytes [
62]. Notably, FIB was found to act not only as an inhibitor of lymphocyte adherence and cytotoxicity against cancer cells [
63] but also as a source of induction of IL-6 [
64]. Taking these studies into account, it is reasonable that patients with a low LFR could have impaired anticancer immunity (in particular those with abnormally elevated IL-6) and attenuated efficacy in killing CCSCs but with enhanced tumor aggressiveness and strengthened tumor protection, which could then lead to a poor prognosis. However, these ideas require further study.
Traditionally, CEA was a reliable prognostic indicator as recommended by ASCO in CRC [
65]. However, its prognostic value is largely limited by its minimal sensitivity, as only 21–36% of patients are positive at diagnosis [
66]. In addition, its efficacy is weaker in patients with type 2 diabetes or with a history of smoking [
67,
68]. Some investigators have looked in normal patients for candidates for CEA, such as CA724 [
69] and CA19-9 [
70], and the Glasgow prognostic score [
71]. However, these reports did not show the AUCs for the tested markers [
69‐
71], and a large proportion of patients with normal CEA would also have normal CA724 (242/295) [
69] and CA19-9 (333/385) [
70]. In our study, the AUC for LFR in CEA normal cases in predicting DFS and OS was 0.67 and 0.75, respectively, meaning that patients with a low LFR also had a significantly inferior outcome. These results indicate that the LFR could also be a useful prognostic indicator in such a scenario.
There are still several limitations to the present study. First, the study is retrospective in nature with a relatively small sample size, and some biases are present. Second, peripheral lymphocytes are highly heterogeneous with distinct or even opposite functions, and some of these cells was have been found to have no impact on survival [
72]. It would be more reasonable to sort a specific cluster, such as CD4+ or CD8+ cells and then examine the value of LFR. Third, both the LC and FIB are dynamic markers in the patients and could be affected by surgery and AC [
73,
74]. Longitudinal measurements of LFR and further validation of its prognostic value are necessary in the future.
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