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Year : 2014  |  Volume : 10  |  Issue : 7  |  Page : 160-166

Prognostic value of circulating C-reactive protein levels in patients with non-small cell lung cancer: A systematic review with meta-analysis

Department of Medical Oncology, Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Hangzhou 310022, China

Date of Web Publication29-Nov-2014

Correspondence Address:
Xinmin Yu
Department of Medical Oncology, Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou 310022
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.145854

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 > Abstract 

Background: The clinical and prognostic significance of C-reactive protein (CRP) in nonsmall-cell lung cancer (NSCLC) remains inconsistent. To clarify a precise determinant of the clinical significance of CRP, we conducted a systematic review and meta-analysis to evaluate the overall risk of elevated CRP for survival in NSCLC.
Materials and Methods: Related studies were identified and evaluated for quality through multiple search strategies. Data were collected from studies comparing overall survival in patients with elevated CRP levels and those having lower levels. The meta-analysis was performed by Review Manager version 5.2 (RevMan; the Cochrane Collaboration, Oxford, England). The pooled hazard ratios (HRs) and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials.
Results: Eight eligible studies involved 1649 patients were ultimately identified. Combined HRs suggested that elevated CRP had an unfavorable impact on survival of patients with NSCLC. The HRs (95% CI) was 1.55 (1.19-2.01) overall, 1.78 (1.33-2.38) in Asian patients, 1.33 (1.00-1.77) in non-Asian patients, 1.78 (1.47-2.15) in primary resectable NSCLC, 1.28 (0.95-1.73) in primary unresectable NSCLC, 1.78 (1.33-2.38) in group of cut-off value <5 mg/L, 1.33 (1.00-1.77) in group of cut-off value ≥10 mg/L.
Conclusions: With the available evidence, CRP might serve as an efficient prognostic indicator in NSCLC. This marker should be taken into consideration in the development of new diagnostic and therapeutic program for NSCLC.

Keywords: C-reactive protein, lung cancer, meta-analysis, prognosis

How to cite this article:
Jin Y, Sun Y, Shi X, Zhao J, Shi L, Yu X. Prognostic value of circulating C-reactive protein levels in patients with non-small cell lung cancer: A systematic review with meta-analysis. J Can Res Ther 2014;10, Suppl S3:160-6

How to cite this URL:
Jin Y, Sun Y, Shi X, Zhao J, Shi L, Yu X. Prognostic value of circulating C-reactive protein levels in patients with non-small cell lung cancer: A systematic review with meta-analysis. J Can Res Ther [serial online] 2014 [cited 2022 May 20];10, Suppl S3:160-6. Available from: https://www.cancerjournal.net/text.asp?2014/10/7/160/145854

 > Introduction Top

Lung cancer continues to be the most frequently diagnosed cancer and the leading cause of cancer-related mortality worldwide, accounting for almost 1.4 million deaths annually. [1] The overall 5-year survival for lung cancer remains at about 15%, which is lower than the mortality rate for other common malignancies, including colon, breast, and prostate cancer. Nonsmall-cell lung cancer (NSCLC) accounts for approximately 80% of lung cancer diagnoses, and the most common forms of NSCLC include adenocarcinoma, squamous cell carcinoma. [2],[3] More than half of NSCLC patients present with advanced, unresectable disease (stage IIIB/IV), despite recent advances in the multidisciplinary treatment, such tumors remain incurable and carries a poor prognosis. [4] Although tumor-node-metastasis (TNM) staging system, age, performance status and weight loss are the most significant clinical parameters to be considered on NSCLC prognosis, the predictive powers of these factors are not optimal. [5] A promising breakthrough to improve the outcome for NSCLC patients is the application of validated biomarkers into clinical management. As a consequence, it is crucial to identify more accurate prognosis and predictive markers that can guide treatment strategies and monitor disease progress, and eventually achieve better prognosis for NSCLC patients.

Chronic airway inflammation plays an important role in the alternations of bronchial epithelium and lung microenvironment, provoking a milieu conducive to pulmonary carcinogenesis and progression of lung cancer. The relationships between inflammation and lung cancer are complex and not yet fully understood. There is mounting evidence suggesting that the association between inflammation and lung cancer is not coincidental, but may indeed be causal. [6],[7],[8] C-reactive protein (CRP) is a representative sensitive marker for inflammatory status which not only display rapid and pronounced rise of its plasma concentration in response to acute inflammation, infection, and tissue damage, [9],[10],[11] but also act as an indicator of chronic inflammation being related to many diseases, including cancers. [12] Serum CRP has been found to be elevated in patients with many malignancies, including lung, [13] breast, [14] pancreas, [15] esophagus, [16] liver, [17] the biliary tract, [18] stomach, [19] and ovary. [20] These results may suggest that high inflammation level can be associated with a higher risk of cancer. During the past decade, researchers focused on extending the clinical use of circulating CRP to the prediction of malignancies. The prognostic significance of serum CRP has also been demonstrated in many forms of cancer, such as colorectal, [21] ovarian, [22] esophageal, [23] pancreatic, [24] and hepatocellular. [25]

Until date, controversy exists concerning the correlation between circulating CRP and prognostic value with respect to NSCLC. Some studies reported that the high expression of serum CRP was correlated with unfavorable prognosis, [26],[27] while some others did not show any significant link between CRP and NSCLC survival. [28],[29] In this study, we performed an updated meta-analysis to give a comprehensive evaluation on the prognostic role of CRP in NSCLC.

 > Materials and methods Top

Searching method and study selection

Two investigators (Yan Sun and Xun Shi) independently searched PubMed and Embase databases using the following search terms "CRP OR inflammation," and "NSCLC." Furthermore, references of retrieved articles and reviews were manually screened for additional studies. Studies were considered eligible if they met the following criteria: (i) Baseline CRP values were measured, (ii) information on survival were provided (studies investigating response rates only were excluded), (iii) when the same author reported results from the same patient population in more than one publication, only the most recent report, or the most complete one, was included. Studies were excluded based on the following criteria: They were (i) Review articles or letters, (ii) non-English-language articles, (iii) laboratory studies, (iv) studies in which necessary data were not provided.

Data extraction and study quality assessment

Two investigators (Jun Zhao and Lei Shi) independently identified eligible trials. When the two investigators discovered different results, an independent expert in oncology made the final decision of study conclusions. Information collected from these studies included first author, year of publication, country of origin, histology, disease stage, sample size, cut-off value, and hazard ratios (HRs) of CRP for overall survival (OS) with its 95% confidence intervals (95% CI) and P value. When HRs were not reported in collected papers, we computed HRs and its 95% CI assuming an exponential distribution of the survival curve. In the estimation of HRs, we applied the published methodology [30] on the graphic software package Engauge (The Engauge is an open source software. We used Engauge Digitizer 4.1 [Qt] in this research) to estimate the logarithm transformed HR and variance from the Kaplan-Meier curves.

We systematically assessed the quality of all the studies included as per the crucial review checklist of the Dutch Cochrane Centre proposed by MOOSE. [31] The key points of the current checklist include: (i) Clear definition of study population and origin of country; (ii) clear definition of study design; (iii) clear definition of outcome assessment, OS, cancer-specific survival and progression-free survival; (iv) clear definition of cut-off for CRP or clear definition of log of CRP and (v) sufficient period of follow-up. Those studies that do not mention all these 5 points were excluded to avoid compromising the quality of a meta-analysis. We performed this meta-analysis in accordance with the guidelines of the Preferred Reporting Items for Systematic Review and Meta-analyses statement.

Statistical analysis

We first tested the statistical heterogeneity between studies (meaningful differences between studies) using the Chi-squared Q-test based on a fixed-effect model. The studies were considered heterogeneous when the P value of the Chi-squared Q-test was <0.10, or when I2 was >50%. When the analyses showed heterogeneity between different studies, a random-effect model was applied to accommodate the heterogeneity. [32] Potential publication bias was assessed with the Begg's test and Egger's test, and graphically presented by funnel plots. All statistical analysis was performed by Review Manager version 5.2 (RevMan; the Cochrane Collaboration, Oxford, England). An HR >1 was regarded as a risk factor for worse survival in patients with elevated CRP serum levels. A two-sided P < 0.05 was considered as significant for all analysis except heterogeneity tests.

 > Results Top

Study selection and characteristics

The selection steps are summarized in the flow chart shown in [Figure 1]. According to the searching strategies, a total of 238 Studies were identified. After a series of screening based on the inclusion/exclusion criteria mentioned above, 8 publications were eventually eligible for the meta-analysis. [26],[ 29],[ 33],[34],[35],[36],[37],[38] All these studies were published in peer-reviewed journals.
Figure 1: Study flow chart for the process of selecting the eligible publications

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A summary of the study characteristics and clinical outcomes is provided in [Table 1]. The data from 8 studies, which involved a total of 1649 patients from the Netherlands, Chinese, Japan, Greece, United Kingdom, and Sweden, were collected. In these eight studies, CRP values were analyzed by the same means in each study. CRP levels were dealt as a dichotomous variable, with different cut-off values. Six studies reported HRs, and the other two studies presented survival curves.{Table 1}

Effect of elevated C-reactive protein on overall survival in overall patients

The results of primary pooled statistics indicated a significant association between elevated CRP and poor OS (HR = 1.55, 95% 1.19-2.01, P = 0.001) based on random-effects model, due to significant heterogeneity (χ2 = 50.09, P < 0.01; I2 = 86%) [Figure 2].
Figure 2: Forest plots in unselected patients. Hazard ratios with 95% confidence interval of overall survival for high C-reactive protein levels as compared with low levels

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Effect of elevated C-reactive protein on overall survival in subgroup analyses

Subgroup analyses were performed by stratifying the included studies by "country of origin," "TNM stage" and "cut-off value."

When stratified by "country of origin", the "Asian" group showed a significant association between elevated CRP and poor OS (HR = 1.78, 95% CI 1.33-2.38, P = 0.0001) [Figure 3]a. The "Non-Asian" group also showed an association between elevated CRP and poor OS (HR = 1.33, 95% CI 1.00-1.77, P = 0.05), but the association was not statistically significant [Figure 3]b.
Figure 3: Forest plots in patients of subgroups. Hazard ratios and 95% confidence intervals of overall survival for high C-reactive protein levels as compared with low levels in (a) the "Asian" group; (b) the "Non-Asian" group; (c) the "primary resectable nonsmall-cell lung cancer (NSCLC)" group; (d) the "primary unresectable NSCLC" group; (e) the cut-off value "≥10 mg/L" group; (f) the cut-off value "<5 mg/L" group

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When stratified by "TNM stage", the "primary resectable NSCLC" group showed a significant association between elevated CRP and poor OS (HR = 1.78, 95% CI 1.47-2.15, P < 0.00001) [Figure 3]c. The "primary unresectable NSCLC" group showed no significant association between elevated CRP and poor OS (HR = 1.28, 95%CI 0.95-1.73, P = 0.11) [Figure 3]d.

When stratified by "cut-off value", the "≥10 mg/L" group showed an association between elevated CRP and poor OS (HR = 1.33, 95% CI 1.00-1.77, P = 0.05), but the association was not statistically significant [Figure 3]e. The "<5 mg/L" group showed a significant association between elevated CRP and poor OS (HR = 1.78, 95% CI 1.33-2.38, P = 0.0001) [Figure 3]f.

Publication bias

Publication bias of the included studies was evaluated by funnel plots. No publication bias was observed in the meta-analysis [Figure 4].
Figure 4: Funnel plots in unselected patients of overall survival

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 > Discussion Top

The role of inflammation in the development of cancer was first revealed in 1863, when Virchow identified leucocyte infiltration in neoplastic tissues that led him to hypothesize that the sites of chronic inflammation were the origin of malignancies. [39] Since then, chronic inflammation of either infectious or noninfectious causes is demonstrated to contribute to about 1 in 4 of all cancer cases. [40] Until now, several such links were extensively proven: Epstein-Barr virus infection for nasopharyngeal carcinoma, [41] liver fluke and primary sclerosing cholangitis for cholangiocarcinoma, [42] infection with hepatitis virus B and hepatitis virus C for hepatocellular carcinoma, [43] UV irradiation-associated skin inflammation for melanoma, [44] Helicobacter pylori bacterial infection for gastric carcinoma, [45] human papilloma virus infection for cervical carcinoma, [46] Barrett's esophagus for esophageal carcinoma, [47] inflammatory bowel diseases for colorectal carcinoma, [48] and inflammation caused by asbestos, infection, smoking and silica for lung cancer. [49] CRP, a representative and sensitive protein that is widely used for the clinical diagnosis of systemic inflammation and is measured by means of reliable standardized assays, shows promise as a potential biomarker for malignancies. CRP was first discovered in 1930 by Tillet and Francis, when they identified this protein in the blood plasma of patients during the acute phase of pneumococcal pneumonia, and named it according to its high binding affinity to the pneumococcal C polysaccharide. [50] CRP is produced solely by hepatocytes and the plasma half-life of CRP is constant under all conditions of health and disease. [51] Therefore, circulating CRP levels will always closely reflect the degree of tissue inflammation.

In this systemic review with meta-analysis, we have combined 8 published studies including 1649 patients with NSCLC to yield summary statistics that indicate that the increased circulating CRP level has a significant association with poor OS in patients with NSCLC. We did further subgroup analyses by dividing the included studies according to "country of origin," "TNM stage" and "cut-off value." We found that the correlation was existed in both Asian and non-Asian study populations. However, the combined HR (1.78) for Asian populations was larger than the combined HR (1.33) for non-Asian populations. This may be explained by the different "cut-off value" between the Asian studies and the non-Asian studies. As we can see in the [Table 1], the four studies conducted in Asian countries all selected "<5 mg/L" as the cut-off value for CRP, and the other four studies conducted in non-Asian countries all selected "≥10 mg/L" as the cut-off value.

The same result was found when the studies were stratified by "cut-off value" for CRP. The combined HR (1.78) for the cut-off value <5 mg/L group was larger than the combined HR (1.33) for the cut-off value ≥10 mg/L group. In the past, circulating CRP levels under 10 mg/L have been regarded as nonmeaningful. During this decade, with the development of a high sensitivity technique, a minor elevation of CRP reflecting chronic low-grade inflammation shows clinically significant. Several studies have revealed an association between minor elevated CRP (3-10 mg/L) and the risk of developing cancers. [52] Considering that this meta-analysis based on retrospective studies, we suggest that more prospective studies need to be conducted to confirm the optimal cut-off value of CRP to predict prognosis for NSCLC.

In addition, subgroup analyses showed that when stratified by "TNM stage", significant association between elevated CRP and poor OS existed in the "primary resectable NSCLC" group (HR = 1.78, 95% CI 1.47-2.15, P < 0.00001). However, no significant association was observed in the "primary unresectable NSCLC" group (HR = 1.28, 95% CI 0.95-1.73, P = 0.11). It is possible that the result in the latter group could have been influenced by the heterogeneity among the three studies included. Heterogeneity might be contributed by the baseline characteristics of the patients, the cut-off value, palliative treatment they have received, and the duration of follow-up. Therefore, the result was tempered, and more research is urgently needed to investigate this doubt.

The underlying molecular mechanism by which circulating CRP is associated with worse outcome of NSCLC is still uncertain. One explanation is that cancer cells can prompt the production of inflammatory proteins. Experimental studies showed that NSCLC cell lines can produce inflammatory factors, such as interleukin-6 (IL-6), IL-8, and tumor necrotic factor-α. [53],[54] Other possible reasons are (1) causality: Elevated CRP levels cause cancer, (2) reverse causality: Occult cancer increases CRP levels, (3) or confounding: A third factor, such as inflammation, increases both CRP levels and the risk of cancer. [55]

There are some limitations of the present meta-analysis that should be noted. First, all data were extracted from published studies, which might result in publication bias and selection bias. Second, due to the lack of relevant prospective study, all the included studies were retrospective. Third, the analysis was based on summary data rather than individual patient data, which tended to overestimate treatment effects. Therefore, the results must be interpreted cautiously when used in clinical practice.

 > Conclusions Top

Our meta-analysis demonstrated that the circulating CRP levels can be used as a useful prognostic predictor for survival in NSCLC. Serum CRP measurements are simple, rapid, cost-effective, and available in daily practice. CRP-lowering agents may have promising roles for the prevention and therapy of NSCLC. More large-scale, high-quality and prospective studies are needed to give more convincing evidence in the future.

 > Acknowledgments Top

This work was supported by Wu Jie Ping Medical Foundation (Grant No. 320.6750.13393).

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