Prognostic value of lymphocyte-to-C-reactive protein ratio in patients with gastric cancer after surgery: a multicentre study

Abstract

Objective

The immune inflammation-based score is recognized as a prognostic marker for cancer. However, the most accurate prognostic marker for patients with gastric cancer remains undetermined. We aimed to evaluate the predictive value of the lymphocyte-to-C-reactive protein ratio for outcomes in gastric cancer patients after radical gastrectomy.

Methods

A total of 607 gastric cancer patients treated at three Chinese institutions were included. Receiver operating characteristic curves were generated, and the areas under the curve were calculated to compare the predictive value among the inflammation-based score, lymphocyte-to-C-reactive protein ratio, C-reactive protein/albumin and neutrophil-lymphocyte, platelet-lymphocyte and lymphocyte-monocyte ratios. Cox regression was performed to determine the prognostic factors for overall survival.

Results

The median follow-up time was 63 months (range: 1–84 months). The optimal cut-off value for lymphocyte-to-C-reactive protein ratio was 0.63. The patients were divided into the LCR <0.63 (LLCR, n = 294) group and the LCR ≥0.63 (HLCR, n = 313) group. LLCR was significantly correlated with poor clinical characteristics. Compared with inflammation-based score, lymphocyte-to-C-reactive protein ratio had the highest areas under the curve (0.695). Patients with LLCR experienced more post-operative complications than the HLCR group (20.4 vs. 12.1%, P = 0.006). Multivariate analysis showed that a higher lymphocyte-to-C-reactive protein ratio (HR: 0.545, 95%CI: 0.372–0.799, P = 0.002) was associated with better overall survival. The HLCR group had higher 5-year overall survival rate than the LLCR group (80.5 vs. 54.9%, P < 0.001).

Conclusions

Preoperative lymphocyte-to-C-reactive protein ratio levels can effectively predict the short-term and oncological efficacy of gastric cancer patients after radical gastrectomy with a predictive value significantly better than other inflammation-based score.

gastric cancer, immune inflammation-based score, lymphocyte-c-reactive protein ratio, complication, prognosis

Introduction

Gastric cancer (GC) is the world’s fifth most common malignant tumour and ranks third in cancer-related mortality (1). At present, treatment for GC patients is still predominantly surgery. Although scholars have made efforts to improve the diagnosis and treatment of GC, long-term survival of patients is still not optimistic, with a high recurrence rate (2). At present, surgeons often evaluate the prognosis according to the American Joint Committee on Cancer (AJCC) staging system, but the survival of patients in the same staging is often inconsistent. It is urgent to explore new ideal predictors to supplement existing staging systems.

Systemic inflammation via host–tumour interactions is the seventh recognized marker of cancer and is closely involved in the development and metastasis of various malignancies (3,4). Recently, several studies have shown that immune inflammation-based scores (IBSs), such as the neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR) and C-reactive protein (CRP)-to-albumin (CAR) ratios, are good prognostic biomarkers in different tumours, including GC (5–9). Powerful biomarkers, while readily available and predict prognosis, should also be able to determine the appropriate treatment options during post-operative care and patient follow-up.

Based on these considerations, several questions need to be addressed before these IBS can be applied in clinical practice in patients with GC. First, although there is growing evidence of the effects of various IBS on the prognosis of GC patients, it is still unclear which combination of inflammatory factors is the best predictor for prognosis. Second, previous studies mainly focused on evaluating the long-term oncology efficacy of IBS, but the predictive value of these markers in the evaluation of postoperative complications has not been further studied. Third, although an increasing number of studies emphasize the prognostic value of various IBS, there is a lack of a uniform cut-off value for evaluating surgical and oncological outcomes. An inflammatory marker with an ideal consistent cut-off value can be more easily generalized in the clinic. Recently, Okugawa et al. found that the lymphocyte-to-CRP ratio (LCR) can effectively evaluate the surgical and oncological outcomes in patients with colorectal cancer (4). However, no one has applied it in Chinese patients with GC. The purpose of this study was to use multi-centric data to investigate whether LCR was superior to traditional IBS in predicting short- and long-term oncology outcomes in patients with GC.

Materials and methods

Population and covariates

Data were selected from a multi-centre cohort comprizing patients with GC between January 2013 and June 2019 who underwent radical gastrectomy at three institutions in China [Fujian Medical University Health System (n = 380), Yijishan Hospital of Wannan Medical College (n = 129) and Qingyang People’s Hospital (n = 98)]. The institutional review boards of all participating institutions approved the study.

The inclusion criteria were defined as follows: presence of primary GC, no receipt of pre-operative chemotherapy and/or radiotherapy, no distant metastasis, no combined malignancy, complete basic patient information and complete routine blood test data. Exclusion criteria were defined as follows: histology showing a tumour type other than adenocarcinoma, remnant GC and tumour invading the adjacent structures (T4b).

Routine blood tests

Blood samples from each patient were obtained within 1 week prior to the surgical resection of their primary tumour.

LCR was calculated as follows: lymphocyte count (number/L)/CRP (mg/L).

NLR was calculated as follows: neutrophil count (number/L)/lymphocyte count (number/L).

PLR was calculated as follows: platelet count (number/L)/lymphocyte count (number/L).

CAR was calculated as follows: CRP (mg/L)/ALB (g/L).

Lymphocyte-to-monocyte ratio (LMR) was calculated as follows: lymphocyte count (number/L)/monocyte count (number/L).

According to the pathologic stage, patients with stage II or above disease were candidates to receive adjuvant chemotherapy during 6 months after surgery. A fluorine-based chemotherapy regimen was recommended. All patients were recommended standard post-operative follow-up, including visits every 3–6 months for the first 2 years, every 6–12 months from the 3rd–5th year and annually thereafter. Most routine follow-up appointments included a physical examination, laboratory testing, chest radiography, abdominopelvic ultrasonography or computed tomography, and positron emission tomography-computed tomography as appropriate, and an annual endoscopic examination was also performed. All the patients were observed until death or the final follow-up date of December 2019.

Overall survival (OS) was defined as the time from surgery to death from any cause. Disease-free survival (DFS) was measured from the date of curative resection to the date of disease recurrence, death from any cause (i.e. cancer-unrelated deaths were not censored) or last follow-up for patients who were still alive. The optimal cut-off values of LCR and other IBSs were determined by receiver operating characteristic (ROC) curves. By calculating the Youden index corresponding to different cut-off values of each IBS in the ROC curves, the corresponding cut-off values of the maximum value of Youden index were used to determine the optimal cut-off values (10). We also performed the DeLong and bootstrap tests to compare two ROC curves (11). Survival analysis was performed using Kaplan–Survival curves which were estimated using the Kaplan–Meier method, and a log-rank test was used to determine significance. Variables associated with OS were identified using multivariate Cox regression models. Stepwise backward variable removal was applied to the multivariate model to identify the most accurate and parsimonious set of variables. Time-dependent ROCs analysis was used to evaluate the discriminatory power of systemic inflammatory factors for time-dependent disease outcomes (12). The data are presented as the mean ± standard deviation for continuous variables and as numbers for categorical variables. The distributions of each continuous and categorical variable were compared using a Student’s t-test, χ2 test or categorical Fisher exact test as appropriate for each variable. All data were processed using SPSS 19.0 (SPSS Inc. Chicago, IL, USA) and R software (version 3.5.3; The R Foundation for Statistical Computing, Vienna, Austria; www.r-project.org). All tests were two-sided with a significance level set at P < 0.05.

Results

Clinicopathological characteristics

Table 1 shows the clinicopathological data of the enrolled patients. A total of 607 patients were included in the analysis, and the median follow-up time was 63 (range: 1–84) months. According to the ROC curve, the optimal cut-off value of LCR was 0.63. Accordingly, the entire cohort was divided into the LCR <0.63 (LLCR) group and LCR ≥0.63 (HLCR) group, with 294 cases and 313 cases, respectively. The LLCR group was significantly correlated with poor clinical characteristics such as larger tumour size and more advanced stage.

Table 1

Clinicopathological characteristics of patients

Variable	Low LCR (n = 294)	High LCR (n = 313)	P value
Age, years	60.7 ± 9.9	56.6 ± 10.6	<0.001
Sex n (%)			0.220
Male	102 (34.7%)	94 (30.0%)
Female	192 (65.3%)	219 (70.0%)
Tumor diameter (mm)	46.1 ± 24.1	37.0 ± 20.2	<0.001
Tumor location n (%)			0.272
Upper	96 (32.7%)	80 (25.6%)
Middle	44 (15.0%)	55 (17.6%)
Lower	129 (43.9%)	147 (47.0%)
Mix	25 (8.5%)	31 (9.9%)
Gastrectomy extent n (%)			0.030
Distal	107 (36.4%)	141 (45.0%)
Total	187 (63.6%)	172 (55.0%)
Pathological type n (%)			0.581
Differentiated	122 (41.5%)	123 (39.3%)
Undifferentiated	172 (58.5%)	190 (60.7%)
Lymphovascular invasion n (%)			0.069
No	156 (53.1%)	189 (60.4%)
Yes	138 (46.9%)	124 (39.6%)
CAR			<0.001
<0.064	48 (16.3%)	234 (74.8%)
≥0.064	246 (83.7%)	79 (25.2%)
LMR			<0.001
<3.91	174 (59.2%)	121 (38.7%)
≥3.91	120 (40.8%)	192 (61.3%)
NLR			<0.001
<3.41	216 (73.5%)	283 (90.4%)
≥3.41	78 (26.5%)	30 (9.6%)
PLR			<0.001
<141.3	99 (33.7%)	193 (61.7%)
≥141.3	195 (66.3%)	120 (38.3%)
Adjuvant chemotherapy			0.566
No	108 (36.7%)	108 (36.7%)
Yes	186 (63.3%)	205 (65.5%)
pT stage n (%)			<0.001
T1	68 (23.1%)	112 (35.8%)
T2	32 (10.9%)	41 (13.1%)
T3	96 (32.7%)	101 (32.3%)
T4	98 (33.3%)	59 (18.8%)
pN stage n (%)			0.002
N0	96 (32.7%)	134 (42.8%)
N1	41 (13.9%)	55 (17.6%)
N2	49 (16.7%)	52 (16.6%)
N3	108 (36.7%)	72 (23.0%)
AJCC8th staging n (%)			0.001
I	78 (26.5%)	118 (37.7%)
II	58 (19.7%)	73 (23.3%)
III	158 (53.7%)	122 (39.0%)

Abbreviations: CRP, C-reactive protein; LCR, lymphocyte-to-CRP ratio; CAR, CRP-to-albumin ratio; LMR, lymphocyte-to-monocyte ratio; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; AJCC, American Joint Committee on Cancer.

Comparison of the prognostic value of LCR with traditional IBS

To compare the predictive power of LCR with other IBS for OS, ROC curves were established for all IBS (Fig. 1). It was found that the LCR had the highest areas under the curve (AUC) value (0.695) compared with other IBS (all P < 0.05) (Table 2). In addition, we generated time-dependent ROC curves for all IBS and found that the AUC of LCR was consistently superior to other IBS throughout the follow-up period (Fig. 2).

Figure 1.

Receiver operating characteristic (ROC) curve analysis to evaluate the predictive value of each combination of systemic inflammatory factors for overall survival (OS) in patients with gastric cancer.

Table 2

Comparison of the AUC between the LCR and other systemic inflammatory factors

Inflammatory factors	AUC	95% Confidence interval	P value*
LCR	0.695	0.657−0.732	-
CAR	0.654	0.615–0.692	0.013
NLR	0.635	0.596–0.674	0.022
LMR	0.631	0.591–0.670	0.023
PLR	0.614	0.574–0.653	0.004

^*Comparison of AUC values between the LCR and other inflammation-based scores was using the Z test method.

Abbreviations: AUC, area under the curve.

Figure 2.

Time-dependent ROC curves for each combination of systemic inflammatory factors. The x-axis represents the months after surgery, and the y-axis represents the estimated area under the ROC curve for survival at the time of interest.

Preoperative LCR levels and post-operative complications

In the LLCR and HLCR groups, there were 60 (20.4%) and 38 (12.1%) patients who experienced post-operative complications, respectively (P = 0.006). Further comparison of various complications revealed that the incidence of various complications in the LLCR group was higher than that in the HLCR group, although the difference was not statistically significant (Table 3).

Table 3

Post-operative complication after surgery

Variable	Low LCR (n = 294)	High LCR (n = 313)	P value
Overall complication	60 (20.4%)	38 (12.1%)	0.006
Abdominal bleeding	6 (2.0%)	4 (1.3%)	0.461
Anastomotic leakage	13 (4.4%)	12 (3.8%)	0.716
Ileus	3 (1.0%)	2 (0.6%)	0.603
Abdominal infection	15 (5.1%)	9 (2.9%)	0.159
Pneumonia	35 (11.9%)	27 (8.6%)	0.183
Liver system	2 (0.7%)	3 (1.0%)	0.705
Urinary system	0 (0.0%)	2 (0.6%)	0.500
Clavien–Dindo classification			0.022
<3	283 (96.3%)	310 (99.0%)
≥3	11 (3.7%)	3 (1.0%)

Univariate and multivariate analyses of factors associated with overall survival

Univariate analysis found that age, tumour size and location, gastrectomy extent, pathological type, lymphovascular invasion, pT stage, pN stage, adjuvant chemotherapy, LCR, CAR, NLR, LMR and PLR were closely related to OS. Further multivariate analysis showed that age, lymphovascular invasion, pT stage, pN stage, adjuvant chemotherapy and LCR were independent risk factors for OS, while other IBS were not (Table 4).

Table 4

Univariate and multivariate cox regression analysis of factors associated with overall survival

Variable	Univariate analysis			Multivariate analysis
	HR	95%CI	P value	HR	95%CI	P value
Age, per y	1.032	1.017–1.048	<0.001	1.017	1.001–1.034	0.043
Tumor diameter, per mm	1.025	1.020–1.031	<0.001	0.997	0.989–1.006	0.562
Sex
Female	1.000
Male	1.065	0.789–1.438	0.681
Tumor location
Upper	1.000			1.000
Middle	0.932	0.619–1.403	0.737	1.348	0.867–2.096	0.185
Lower	0.644	0.462–0.898	0.010	1.075	0.634–1.825	0.788
Mix	1.219	0.770–1.930	0.399	1.556	0.957–2.529	0.075
Gastrectomy extent
Distal	1.000			1.000
Total	1.654	1.225–2.233	0.001	0.822	0.493–1.372	0.454
Pathological type
Differentiated	1.000			1.000
Undifferentiated	1.573	1.170–2.116	0.003	0.991	0.710–1.382	0.957
Lymphovascular invasion
NO	1.000			1.000
Yes	4.662	3.412–6.370	<0.001	1.913	1.337–2.738	<0.001
Adjuvant chemotherapy
No	1.000			1.000
Yes	0.494	0.355–0.687	<0.001	0.588	0.402–0.860	0.006
LCR
<0.63	1.000			1.000
≥0.63	0.347	0.257–0.470	<0.001	0.545	0.372–0.799	0.002
CAR
<0.064	1.000			1.000
≥0.064	2.248	1.663–3.039	<0.001	1.118	0.792–1.580	0.526
LMR
<3.91	1.000			1.000
≥3.91	0.448	0.335–0.600	<0.001	0.860	0.618–1.196	0.370
NLR
<3.41	1.000			1.000
≥3.41	2.654	1.967–3.580	<0.001	1.399	0.978–2.000	0.066
PLR
<141.3	1.000			1.000
≥141.3	1.971	1.472–2.640	<0.001	1.302	0.937–1.809	0.116
pT
T1	1.000			1.000
T2	4.271	1.770–10.306	0.001	2.806	1.080–7.288	0.034
T3	11.653	5.639–24.081	<0.001	5.496	2.256–13.389	<0.001
T4	21.860	10.614–45.035	<0.001	6.710	2.639–17.065	<0.001
pN stage n (%)
N0	1.000			1.000
N1	4.223	2.335–7.636	<0.001	2.050	1.060–3.965	0.033
N2	5.038	2.845–8.922	<0.001	2.309	1.224–4.359	0.010
N3	14.457	8.790–23.779	<0.001	4.645	2.491–8.663	<0.001

Overall survival, DFS and subgroup analysis

The 5-year OS of the HLCR group was significantly higher than that of the LLCR group (80.5 vs. 54.9%, respectively, P < 0.001; Fig. 3). Based on the 7th AJCC-TNM stratified analysis, we found consistent results in patients with stage I, II and III with the 5-year OS of the HLCR group significantly higher than that of the LLCR group (99.2 vs. 93.6%, P = 0.003; 82.2 vs. 69.3%, P < 0.001; 61.0 vs. 30.8%, P < 0.001, respectively). The similar findings were observed in the analysis for DFS (Fig. S1). The 5-year DFS of the HLCR group was significantly better than that of the LLCR group (75.3 vs. 49.0%, respectively, P < 0.001).

Figure 3.

Kaplan–Meier analysis of OS according to the lymphocyte-to-CRP ratio (LCR): (A) overall population, (B) stage I, (C) stage II and (D) stage III.

Discussion

Since Virchow first discovered the relationship between inflammation and tumours (3), an increasing amount of evidence indicates that tumour progression is not only related to the intrinsic characteristics of tumour cells but is also inseparable from the body’s inflammatory immune response (13). The characteristics of cancer-related inflammation include the infiltration of inflammatory cells, production of inflammatory factors in tumour tissues, tissue remodelling, tissue repair and angiogenesis (14). Systemic inflammatory indicators play a key role in promoting cancer development. IBSs, such as NLR and PLR, obtained from whole blood cells are related to tumour progression (neutrophils and platelets) and anti-tumour immunity (lymphocytes) (15,16). These theories have led to in-depth studies of IBS by scholars in recent years, and IBS has been confirmed to be closely related to the long-term survival of many tumours (5,9,15,17,18).

Proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6, IL-8 and tumour necrosis factor α, are upregulated as part of the inflammatory response in the body. CRP is mainly produced by liver cells, and its rapid increase in serum concentration is related to the abovementioned pro-inflammatory factors (19). These pro-inflammatory factors enhance the progression and metastasis of malignant tumours by accelerating angiogenesis (20,21). Pro-inflammatory cytokines also mediate the recruitment of circulating myeloid cells to the tumour, and CD8+ T cells are decreased due to direct or indirect immunosuppression by intratumour myeloid cells (19). Thus, systemic inflammation is typically characterized by an increase in circulating neutrophils and monocytes and a decrease in circulating lymphocytes. Peripheral blood lymphocytes play a key role in the host cell immune response to tumours and can also be used to assess patient health.

Previous research by Clark et al. showed that a low pre-operative lymphocyte level rather than NLR is a good predictor of poor prognosis for pancreatic ductal adenocarcinoma (22). When combining lymphocytes and CRP, several scholars found that LCR was the most prognostic when compared with other IBS for colorectal cancer patients (4,23,24). The present study also found that LCR is superior to previous IBS (CAR, NLR, LMR and PLR) in assessing the overall survival of GC and can make a good distinction between overall survival within each stage and complement the existing AJCC staging system to a certain extent.

Several studies have shown that pre-operative systemic inflammatory reactions via host–tumour interactions are a potential predictor of post-operative complications in cancer patients (25,26). However, few studies have reported an association between preoperative IBS and post-operative complications in patients with GC. Considering this evidence together with the novel findings from our study, LCR could reflect both the immunological response and systemic inflammation, where LLCR represents an impaired immunological response and/or enhancement of systemic inflammation. More attention should be paid to patients with LLCR perioperatively.

Recently, a similar study on LCR in GC patients has been reported (27), which is a single-center retrospective study. Compared with the previous study, the present study has the following innovative points. For the first time, we used the multi-center data from China and confirmed the predictive value of LCR on post-operative complications and long-term prognosis of GC patients by comparing LCR with other inflammatory indicators. The level of evidence-based medicine of multi-center study is theoretically superior to that of single-center study (28), which makes the results more universal and applicable. Secondly, the study by Okukaway et al. showed that 296 patients (53.7%) were pathologic Stage I GC. However, advanced GC accounted for more than 80% of cases in China in contrast to early GC, which accounted for 60% of cases in Japan and South Korea (29,30). Therefore, samples from different populations are still needed to assess the role of LCR level in the prognosis of GC patients. In our study, only 32.7% of the patients were Stage I GC. This study further validated the predictive value from another perspective and provided evidence for the application of LCR in the other population. Finally, the study by Okukaway et al. included 82 (14.9%) patients with pathologic stage IV GC. However, patients with metastatic diseases always receive a combination of treatments including pre-operative chemotherapy, leading to changes in inflammatory markers in the blood, which may result in biases (31). For this reason, our study only included patients for whom underwent curative gastrectomy was performed and for whom post-operative pathology confirmed stages I–III, which made the results more stable.

Lower preoperative LCR using our optimal cut-off threshold was an independent prognostic factor for both OS and DFS and also an independent risk factor for post-operative complications in patients with GC undergoing radical gastrectomy. For clinical uses, an ideal prognostic biomarker should have the following distinguishing features. First, it could identify a patient’s prognosis independent of conventional classifications (i.e. TNM classification) to improve oncological outcome. Second, it could also predict a patient’s response or adverse effect to a specific treatment, thereby improving their prognosis and quality of life (i.e. post-operative complications). Third, prognostic biomarker should be readily available, simplified and inexpensive and use objective approaches to inform clinical decision-making and stratify patients into different risk groups (32). This study successfully validated the clinical feasibility of preoperative LCR using consistent cut-off value for multiple outcomes in GC patients undergoing radical gastrectomy, which will contribute to the clinical practice. Previous studies have shown that a constant cut-off value of an inflammatory marker for predicting surgical and oncological outcomes is more suitable for clinical use (4,33,34).

There are some limitations to the present study. First, this was a retrospective multi-centre study, and there was inevitably some bias. Second, we only used data from China, and large samples of western data are still needed to further validate the findings. In addition, there is a lack of basic research exploring the specific mechanism by which LCR affects the oncological efficacy of GC patients. Third, this study excluded patients who received neoadjuvant therapy because neoadjuvant therapy may have a great impact on pre-operative blood indexes. The role of LCR in patients receiving neoadjuvant therapy is expected to be evaluated in the future using prospective large sample multi-centre data. Finally, although the present study included patients from multiple centers in China, further validation of the prognostic value of LCR through global big data sets is warranted in the future, especially data from western cohorts. Nonetheless, to our knowledge, this study is the first to report that LCR is closely related to complications and prognosis after radical gastrectomy in Chinese cohorts.

Conclusion

Pre-operative LCR could effectively predict the short- and long-term oncological efficacy for GC patients after radical gastrectomy and had significantly better predictive value than other traditional IBS. Patients with LLCR may benefit from more aggressive post-operative care and rigorous follow-up strategies.

Conflict of interest statement

None declared.