Ann Surg Treat Res. 2021 Jun;100(6):338-346. English.
Published online Jun 01, 2021.
Copyright © 2021, the Korean Surgical Society
Original Article

Clinical significance and prognostic value of C-reactive protein/albumin ratio in gastric cancer

Qian Yu,1,* Ke-zhi Li,2,* Yan-jun Fu,1 Yanping Tang,2 Xin-qiang Liang,2 Zhi-qing Liang,3 and Ji-hong Bai1
    • 1Department of Pharmaceutics, Affiliated Hospital of Guilin Medical University, Guilin, China.
    • 2Department of Research, Guangxi Medical University Cancer Hospital, Nanning, China.
    • 3Department of Endocrinology, Affiliated Hospital of Guilin Medical University, Guilin, China.
Received December 14, 2020; Revised March 08, 2021; Accepted March 23, 2021.

Annals of Surgical Treatment and Research is an Open Access Journal. All articles are distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

This study was aimed to evaluate the clinical significance and prognostic value of CRP/albumin ratio (CAR) in patients with gastric cancer.

Methods

The data of 205 gastric cancer patients who underwent surgery was analyzed retrospectively. The association of CAR with the clinical features and prognostic value in gastric cancer was analyzed. The data of this study was combined with previous studies to further determine the prognostic value of CAR in patients with gastric cancer using a meta-analysis method.

Results

Cox analysis revealed that preoperative CAR was an independent prognosis indicator in patients with gastric cancer. High expression of CAR indicated a shorter survival time than in those with lower expression. CAR has a higher prognostic value in the 1-, 3-, and 5-year overall survival in patients with gastric cancer. CAR showed significant difference regarding the gastric cancer patients' age, M stage, and clinical stage. The discriminate value of CAR in M stage of gastric cancer was high (area under the curve, 0.809). A meta-analysis combining previous data and our data showed that preoperative CAR demonstrated a significant association with the overall survival of patients with gastric cancer.

Conclusion

This study demonstrated that preoperative CAR could serve as an important prognostic indicator in patients with gastric cancer.

Keywords
C-reactive protein/albumin ratio; Preoperative; Prognosis; Stomach neoplasms

INTRODUCTION

As one of the most common digestive malignant tumors, gastric cancer accounts for about 5.7% of the total cancer cases according to the GLOBOCAN 2018 data [1]. Although the survival of some patients with gastric cancer improved with the advancement of the therapeutic methods, those patients at a later stage of cancer continue to have a poor prognosis [2]. Therefore, finding effective prognostic indicators for these patients could help clinicians make proper treatment decisions.

Currently, some serum tumor indicators such as CA 125, CA 153, CA 19-9, and CEA have been applied to assess the diagnostic and prognostic values in patients with gastric cancer. For example, the elevation of CA 19-9 level was correlated with female sex and presence of lymph node metastasis in gastric cancer, and elevation of CEA level was an independent risk factor for poor prognosis of early gastric cancer [3]. However, these indicators were subject to low sensitivity and specificity for different stages of cancer [3, 4]. In addition, some novel indicators calculated from conventional biomarkers, such as neutrophil lymphocyte ratio (NLR) [5, 6], platelet lymphocytes ratio (PLR) [7], and CRP/albumin ratio (CAR) [8, 9], have been reported to enhance the prognostic values in patients with various cancers. Among these indicators, the clinical significance and prognostic value of CAR in gastric cancer continue to require further elucidation.

CAR is a novel inflammation-based prognostic indicator; the high value of CAR was associated with poor outcome in various diseases, including sepsis [10], pancreatitis [11], and some cancers [12]. The prognostic value of CAR in patients with gastric cancer has also been explored [13, 14, 15]. However, the robustness of previous studies still requires validation through further studies. Therefore, in order to derive a more precise assessment of the prognostic value of CAR in gastric cancer, we analyzed the data of gastric cancer and combined our data with previous data, which may further verify the role of CAR in gastric cancer.

METHODS

Selection of gastric cancer patients

The data of patients with gastric cancer who underwent surgery was retrospectively analyzed at the Guangxi Medical University Cancer Hospital (Guilin, China) between January 2015 and October 2019. Inclusion criteria are (1) diagnosis of gastric cancer was confirmed histologically and (2) all gastric cancer patients underwent surgical treatment. Patients with autoimmune diseases, infectious diseases, severe hematologic diseases, or major organ failure were excluded. This study was approved by the Ethics Committee of the Guangxi Medical University Cancer Hospital with a waiver for informed consent (No. KY2020015).

Data collection and calculation

The clinical features of gastric cancer were collected including patient age, sex, tumor location, differentiation grade, and TNM stage. TNM stage was defined based on the American Joint Committee on Cancer criteria, 8th edition [16]. Preoperative laboratory blood parameters, such as CRP, albumin, neutrophil, lymphocytes, platelet, and the tumor biomarkers (CEA, CA125, CA153, and CA 19-9) were collected. The NLR, PLR, and CAR were calculated. Overall survival (OS) was calculated from the date of surgery to the date of death or last follow-up.

Statistical analysis

Continuous data was presented as a median and interquartile range from 25th to 75th percentile. Mann-Whitney U-test or Student t-test were used to compare continuous variables between the 2 groups when appropriate. The chi-square test was applied to categorical variables between groups. Kaplan-Meier curve and the log-rank test were used to evaluate the survival time between the 2 groups. Cox regression analysis was employed to identify the prognostic indicators in patients with gastric cancer. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) was conducted to assess the prognostic value of CAR. All statistical tests were 2-sided and P-values of <0.05 were considered statistically significant. The statistical analyses were performed using IBM SPSS Statistics ver. 21.0 (IBM Corp., Armonk, NY, USA) and R ver. 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria).

Meta-analysis for the data

The performance of meta-analysis on the prognostic value of CAR in gastric cancer was conducted as in our previous study [17]. Briefly, the relevant articles were retrieved and assessed from the databases (PubMed, Web of Science, and Chinese National Knowledge Infrastructure before October 2020, using “C-reactive protein/albumin ratio,” “CAR,” or “gastric cancer” as search terms) based on certain criteria and the data of these articles (author's name, number of patients, cutoff value of CAR, stage of cancer, follow-up and hazard ratio [HR] values for survival) was extracted. The differences among the subgroups were assessed using meta-regression analysis. The random-effects model (DerSimonian-Laird method) was used to combine the HRs if there was significant heterogeneity across the studies; otherwise, a fixed-effects model (Mantel-Haenszel method) was conducted. R ver. 3.5.1 was used to conduct the meta-analysis. The P-values of <0.05 were considered statistically significant.

RESULTS

Clinical characteristics of the study populations

The patient selection flow chart is shown in Fig. 1. A total of 205 patients with gastric cancer who underwent surgical treatment were finally selected in this study. The median age of the patients was 58 years. The median follow-up was 44 months (1–64 months). All of 124 patients were alive and 81 patients dead during the follow-up period. The details of patients with gastric cancer are listed in Table 1.

Fig. 1
The patient selection flowchart of the present study. CAR, CRP/albumin ratio.

Table 1
Clinical characteristic of the patients with gastric cancer

Univariate and multivariate Cox regression analysis for the clinical features

The univariate Cox regression analysis was performed by including the clinical features, including patient sex, age, histological grade, TNM stage, and laboratory variables. The results showed that patients' age, CEA, CA 125, CA 153, CA 19-9, high-sensitivity CRP, N stage, M stage, NLR, and CAR were significantly associated with the survival of patients with gastric cancer. Then, the multivariate Cox regression analysis for these variables showed that patient age (HR, 1.04; 95% confidence interval [CI], 1.01–1.06), M stage (HR, 3.56; 95% CI, 1.89–6.07), and CAR (HR, 1.86; 95% CI, 1.13–3.01) were considerably associated with the survival in patients with gastric cancer (Table 2).

Table 2
Identify prognostic biomarkers for patients with gastric cancer using Cox analysis

Survival analysis and prognostic value of CAR in patients with gastric cancer

Using the median value as cutoff (CAR, 0.022), the Kaplan-Meier curve and log-rank test revealed that, patients with high values of CAR have shorter survival time than those with low values (Fig. 2A). We next determined the prognostic value of CAR in gastric cancer patients in different survival times, and found that CAR has a good performance in predicting the 1-, 3-, and 5-year survival in patients with gastric cancer, with the AUC as 0.758, 0.742, and 0.787, respectively (Fig. 2B). In order to evaluate the effect of different stage of cancer on the prognostic value of CAR, we conducted subgroup analysis by dividing the patients into 3 subgroups based on the clinical stage (stage I, stage II + III, and stage IV), and the results failed to show that CAR was associated with the prognosis of patients in these subgroups (P > 0.05).

Fig. 2
(A) Kaplan-Meier curve for the CRP/albumin ratio (CAR) in patients with gastric cancer using median value as a cutoff. (B) The prognostic value of CAR in predicting the 1-, 3-, and 5-year survival in patients with gastric cancer. ROC, receiver operating characteristic; AUC, area under the curve.

Association of CAR with the clinical features in gastric cancer

The association of CAR with the clinical features of gastric cancer, including patient's age, sex, histological grade, TNM stage, and clinical stage, were analyzed, respectively. As Table 3 showed, CAR value was remarkably increased in patients with M1 stage compared with M0 stage (P < 0.001), and elevated in stage IV compared with stage I and stage II + III (P = 0.001); however, no obvious differences were observed between CAR and other clinical features (P > 0.05).

Table 3
Association of CAR with the clinical features in gastric cancer

Discrimination value of CAR in different M stage of gastric cancer

Since there was a significant difference of CAR value in M stage and clinical stage of patients, we further evaluated the discriminate value of CAR in M stage and clinical stage of gastric cancer; the ROC method was used to calculate the AUC of CAR. As Fig. 3 illustrates, CAR could reach a high predictive value in different M stage with the AUC value of 0.809, and the predictive value in the different clinical stage was moderate with the AUC value of 0.679.

Fig. 3
Discriminated value of C-reactive protein/albumin ratio (CAR) in different TNM stage of gastric cancer. (A) M stage (M0 vs. M1; cutoff: 0.357). (B) Clinical stage (I vs. II + III + IV; cutoff: 0.048). ROC, receiver operating characteristic; FPR, false positive rate; TPR, true positive rate; AUC, area under the curve.

Meta-analysis for the prognostic value of CAR in gastric cancer

Seven studies [13, 14, 15, 18, 19, 20, 21] with 1,978 patients that evaluated the prognostic value of CAR in patients with gastric cancer were included in the meta-analysis. The details of included studies are listed in Table 4. All the data of CAR in predicting the prognosis of patients was extracted from multivariate Cox regression. By combing these data with our data, we found that CAR was significantly associated with the survival of patients with gastric cancer (HR, 1.94; 95% CI, 1.67–2.27; Mantel-Haenszel method, I2 = 0, P heterogeneity = 0.891) (Fig. 4A). The subgroup analysis by dividing the cutoff value into <0.1 or >0.1 showed that both of CAR with different cutoff value have significant prognostic value in gastric cancer (both P < 0.05, Mantel-Haenszel method). Meta-regression analysis revealed that no significant difference between these 2 subgroups (P > 0.05) (Fig. 4B), suggesting that different cutoff value did not affect the prognostic value of CAR in patients with gastric cancer. No publish bias was found across these studies (P > 0.05).

Fig. 4
Forest plot of the Meta analysis. (A) Forest plot of hazard ratio (HR) for the association of CRP/albumin ratio (CAR) with overall survival (OS) in patients with gastric cancers. (B) Forest plot of HR for the association of CAR with OS in gastric cancers with different cutoff values. TE, treatment estimate; seTE, standard error of TE; CI, confidence interval.

Table 4
Characteristics of included studies

DISCUSSION

The development and progression of cancer is a complicated process, and many factors have been contributed to gastric carcinogenesis. Among them, systemic inflammatory response and nutritional status are 2 important contributors [22]. Evidences showed that CAR was an important inflammation-based prognostic indicator that was associated with the survival of various cancers [23, 24]. In the present study, we found that CAR was an important prognostic indicator in patients with gastric cancer, which was in agreement with previous studies [13, 14, 21]. We also found that CAR has a higher prognostic value in predicting the 1-, 3- and 5-year survival of patients. In agreement with previous studies [13, 15, 21], our results showed that CAR was associated with M stage and clinical stage of gastric cancer, and the discriminate value for the different M stage was higher, suggesting that the CAR might be used to differentiate the M stage of gastric cancer.

Serum CRP is an acute-phase protein and reported to be a sensitive prognostic indicator in a variety of inflammatory diseases and cancers [25, 26]. A study has shown that reduction of CRP as an early predictor of postoperative complications and a reliable discharge indicator after gastrectomy for gastric cancer [27]. On the other hand, serum albumin level is an indicator of body nutrition status, low albumin level indicates a malnutrition status and often second to patients with gastrointestinal cancers, especially those at an advanced stage [28, 29]. CAR is calculated based on both serum CRP and albumin level, which is more reliable than single one in predicting the outcome of the malignancy [30]. Although other inflammation-based prognostic indicators, such as NLR and PLR, have been shown to associate with the prognosis in patients with gastric cancer, the present study failed to confirm the prognostic value of them by using multivariate Cox regression analysis. CAR also reflects immune and nutritional status of the patients, while other prognostic indicators such as prognostic nutritional index (PNI) were also found to be associated with the prognosis of the patients with cancers. A previous study reported a comparison of CAR with PNI in 363 cancer and non-cancer patients which showed that PNI and CAR were both useful to predict the long-term survival of patients. Moreover, CAR has better performance than PNI in predicting the short-term survival of patients. These results suggest that these indicators might not stable in predicting the survival of patients with gastric cancer compared with CAR.

TNM stage is one of the most important criteria in predicting the prognosis of patients with various cancers, and many studies reported that inflammation-based prognostic indicators, including NLR, PLR, and CAR, were associated with the TNM stage in gastric cancer. For example, Toiyama et al. [15] reported that CAR was significantly increased in gastric cancer with lymph node metastasis and poor differentiation. Liu et al. [19] observed that CAR was associated with the lymph node metastasis and clinical stage of gastric cancer. A similar result was found in the report of Mao et al. [13]. However, in the present study, we failed to show the association with the clinical features, including the TNM stage, which was similar to the report by Saito et al. [14], indicating that the change of CAR might be independent of the TNM stage. Moreover, our results showed that CAR has a moderate value in discriminating the M stage (M0 and M1) and clinical stage (I and II + III + IV), which may help to identify the patients who are at high risk and provide them proper treatment. In this study, the results indicated that only M stage, but not T stage or N stage, was as in independent prognostic factor in predicting the prognosis of patients. We speculated that the relative sample size might explain these results, and a larger cohort is necessary to verify these results.

As in other studies, our results were based on a single center, which may be subject to several limitations. In order to achieve a more robust conclusion, we conducted a meta-analysis by combing our data with previous studies. As shown from the meta-analysis, including 7 studies with larger gastric cancer patients, CAR was shown to be significantly associated with the survival of patients with gastric cancer, which further confirmed the prognostic value of CAR in these patients. Unlike other novel prognostic biomarkers, CRP and albumin are routine laboratory tests using blood samples in clinical practice. Thus, the results of CAR can be obtained easily and do not add extra costs to the patients, making it an attractive biomarker for the prognosis of gastric cancer. For instance, a patient with high CAR should be considered for surgery or added necessary adjuvant chemotherapy. In addition, the follow-up interval after treatment must be shorter compared with those of low CAR values. Therefore, CAR could be considered as an indicator of simplicity, cheapness, and easy availability in clinical settings.

However, we acknowledged several limitations in the present study, which might reduce the robustness of the conclusion. First, our study was a retrospective design, single-center study, which potentially leads to selection bias. Second, many factors affect the serum levels of CRP and albumin, but we could not adjust these confounding factors in this study. Third, the postoperative therapy was different across the patients, which might also induce bias. Fourth, American Society of Anesthesiologists and Eastern Cooperative Oncology Group were important indicators used to evaluate the patient's condition before surgery; however, due to lack of data in our center, we could not analyze the relation of these scores with the CAR. Therefore, a future larger-scale study with prospective design by addressing the aforementioned issues is warranted to validate our findings.

In conclusion, the present study demonstrates that preoperative CAR is associated with the prognosis of patients with gastric cancer after surgery, which may help to provide proper treatment for patients.

Notes

Fund/Grant Support:This study was partially supported by research funding from the National Natural Science Foundation of China (No.81260078); Guangxi Natural Science Foundation Grant (2014GXNSFAA118152).

Conflicts of Interest:No potential conflict of interest relevant to this article was reported.

Author Contribution:

  • Conceptualization: JB, ZL, QY.

  • Formal Analysis: QY, KL, YT, XL.

  • Investigation: QY, YF.

  • Methodology: XL.

  • Project Administration: XL.

  • Writing — Original Draft: QY, JB.

  • Writing — Review & Editing: All authors.

References

    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424.
    1. Hundahl SA, Phillips JL, Menck HR. The National Cancer Data Base Report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy: Fifth Edition American Joint Committee on Cancer staging, proximal disease, and the “different disease” hypothesis. Cancer 2000;88:921–932.
    1. Feng F, Tian Y, Xu G, Liu Z, Liu S, Zheng G, et al. Diagnostic and prognostic value of CEA, CA19-9, AFP and CA125 for early gastric cancer. BMC Cancer 2017;17:737
    1. Tian SB, Yu JC, Kang WM, Ma ZQ, Ye X, Cao ZJ, et al. Combined detection of CEA, CA 19-9, CA 242 and CA 50 in the diagnosis and prognosis of resectable gastric cancer. Asian Pac J Cancer Prev 2014;15:6295–6300.
    1. Mellor KL, Powell AG, Lewis WG. Systematic review and meta-analysis of the prognostic significance of Neutrophil-Lymphocyte Rat io (NLR) af ter R0 gastrectomy for cancer. J Gastrointest Cancer 2018;49:237–244.
    1. Kim JH, Han DS, Bang HY, Kim PS, Lee KY. Preoperative neutrophil-to-lymphocyte ratio is a prognostic factor for overall survival in patients with gastric cancer. Ann Surg Treat Res 2015;89:81–86.
    1. Xu Z, Xu W, Cheng H, Shen W, Ying J, Cheng F, et al. The prognostic role of the platelet-lymphocytes ratio in gastric cancer: a meta-analysis. PLoS One 2016;11:e0163719
    1. Tanaka H, Tamura T, Toyokawa T, Muguruma K, Kubo N, Sakurai K, et al. C-reactive protein elevation ratio as an early predictor of postoperative severe complications after laparoscopic gastrectomy for gastric cancer: a retrospective study. BMC Surg 2019;19:114
    1. Xu BB, Lu J, Zheng ZF, Xie JW, Wang JB, Lin JX, et al. The predictive value of the preoperative C-reactive proteinalbumin ratio for early recurrence and chemotherapy benefit in patients with gastric cancer after radical gastrectomy: using randomized phase III trial data. Gastric Cancer 2019;22:1016–1028.
    1. Ranzani OT, Zampieri FG, Forte DN, Azevedo LC, Park M. C-reactive protein/ albumin ratio predicts 90-day mortality of septic patients. PLoS One 2013;8:e59321
    1. YXMLLink_XYZlmaz EM, Kandemir A. Significance of red blood cell distribution width and C-reactive protein/albumin levels in predicting prognosis of acute pancreatitis. Ulus Travma Acil Cerrahi Derg 2018;24:528–531.
    1. Wu J, Tan W, Chen L, Huang Z, Mai S. Clinicopathologic and prognostic significance of C-reactive protein/albumin ratio in patients with solid tumors: an updated systemic review and metaanalysis. Oncotarget 2018;9:13934–13947.
    1. Mao M, Wei X, Sheng H, Chi P, Liu Y, Huang X, et al. C-reactive protein/albumin and neutrophil/lymphocyte ratios and their combination predict overall survival in patients with gastric cancer. Oncol Lett 2017;14:7417–7424.
    1. Saito H, Kono Y, Murakami Y, Shishido Y, Kuroda H, Matsunaga T, et al. Prognostic significance of the preoperative ratio of C-Reactive protein to albumin and neutrophil-lymphocyte ratio in gastric cancer patients. World J Surg 2018;42:1819–1825.
    1. Toiyama Y, Shimura T, Yasuda H, Fujikawa H, Okita Y, Kobayashi M, et al. Clinical burden of C-reactive protein/albumin ratio before curative surgery for patients with gastric cancer. Anticancer Res 2016;36:6491–6498.
    1. Amin MB, Edge SB, Greene F, Byrd DR, Brookland RK, Washington MK, et al. In: AJCC Cancer Staging Manual. 8th ed. Cham, Switzerland: Springer; 2017.
    1. Fu YJ, Li KZ, Bai JH, Liang ZQ. C-reactive protein/albumin ratio is a prognostic indicator in Asians with pancreatic cancers: a meta-analysis. Medicine (Baltimore) 2019;98:e18219
    1. Kudou K, Saeki H, Nakashima Y, Kamori T, Kawazoe T, Haruta Y, et al. C-reactive protein/albumin ratio is a poor prognostic factor of esophagogastric junction and upper gastric cancer. J Gastroenterol Hepatol 2019;34:355–363.
    1. Liu X, Sun X, Liu J, Kong P, Chen S, Zhan Y, et al. Preoperative C-reactive protein/ albumin ratio predicts prognosis of patients after curative resection for gastric cancer. Transl Oncol 2015;8:339–345.
    1. Toyokawa T, Muguruma K, Tamura T, Sakurai K, Amano R, Kubo N, et al. Comparison of the prognostic impact and combination of preoperative inflammation-based and/or nutritional markers in patients with stage II gastric cancer. Oncotarget 2018;9:29351–29364.
    1. Liu HC, Chen YJ, Xu YF, Xu ZH, Xu CY. Effect of preoperative ratio of C reactive protein to albumin on prognosis of patients with gastric cancer. Chin J Lab Diagn 2018;22:27–29.
    1. Abdi E, Latifi-Navid S, Zahri S, Yazdanbod A, Pourfarzi F. Risk factors predisposing to cardia gastric adenocarcinoma: insights and new perspectives. Cancer Med 2019;8:6114–6126.
    1. Liu Y, Chen S, Zheng C, Ding M, Zhang L, Wang L, et al. The prognostic value of the preoperative c-reactive protein/albumin ratio in ovarian cancer. BMC Cancer 2017;17:285
    1. Uchimoto T, Komura K, Fujiwara Y, Saito K, Tanda N, Matsunaga T, et al. Prognostic impact of C-reactive protein-albumin ratio for the lethality in castration-resistant prostate cancer. Med Oncol 2019;37:9
    1. Khedher S, Fouthaili N, Maoui A, Lahiani S, Salem M, Bouzid K. The diagnostic and prognostic values of C-reactive protein and procalcitonin during bacterial infections in decompensated cirrhosis. Gastroenterol Res Pract 2018;2018:5915947
    1. Chen IM, Johansen AZ, Dehlendorff C, Jensen BV, Bojesen SE, Pfeiffer P, et al. Prognostic value of combined detection of serum IL6, YKL-40, and C-reactive protein in patients with unresectable pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2020;29:176–184.
    1. Lee SH, Kim KH, Choi CW, Kim SJ, Kim DH, Choi CI, et al. Reduction rate of C-reactive protein as an early predictor of postoperative complications and a reliable discharge indicator after gastrectomy for gastric cancer. Ann Surg Treat Res 2019;97:65–73.
    1. Takeda K, Umezawa R, Takahashi N, Matsushita H, Kozumi M, Ishikawa Y, et al. Impact of change in serum albumin level during and after chemoradiotherapy in patients with locally advanced esophageal cancer. Esophagus 2018;15:190–197.
    1. Lim WS, Roh JL, Kim SB, Choi SH, Nam SY, Kim SY. Pretreatment albumin level predicts survival in head and neck squamous cell carcinoma. Laryngoscope 2017;127:E437–E442.
    1. Dupré A, Malik HZ. Inf lammation and cancer: what a surgical oncologist should know. Eur J Surg Oncol 2018;44:566–570.

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