Asia-Pacific Journal of Clinical Oncology 2014

doi: 10.1111/ajco.12091


Elevated serum C-reactive protein, carcinoembryonic antigen and N2 disease are poor prognostic indicators in non-small cell lung cancer Xue-Feng NI,1* Ping WU,2* Chang-Ping WU,1 Mei JI,1 Jun WU,1 Xiao-Fang GU3 and Zhen-Xing JIANG3 Departments of 1Oncology, 2Pharmacology and 3Radiology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu Province, China

Abstract Aim: To assess the prognostic value of mediastinal lymph node metastases (N2 disease), carcinoembryonic antigen (CEA) levels and C-reactive protein (CRP) in non-small cell lung cancer (NSCLC), according to the 7th edition of the TNM classification. Methods: Newly diagnosed stage III-IV NSCLC were enrolled, including 75 patients with malignant pleural effusion. The relationship between serum CRP levels and other relevant variables such as sex, Eastern Cooperative Oncology Group status, smoking status, initial staging, N2 disease, serum albumin, white blood cell count, platelet count, CEA, comorbidity and pathology were analyzed. Univariate and multivariate analyses were performed to find prognostic markers using Cox’s proportional hazards model. Results: Of the 127 patients enrolled, 55 (43%) had elevated CRP levels. There was a significant correlation between serum CRP level and platelet count (P = 0.011). Median overall survival (OS) in the normal CRP group was significantly longer than in the high CRP group (15.7 months vs 9.1 months, P = 0.013). Hypoalbuminemia (P = 0.047), higher CEA (P = 0.043) and N2 disease (P = 0.040) were additional prognostic factors on univariate analysis. On multivariate analysis an elevated CRP serum level (HR = 1.796; P = 0.005), higher CEA (HR = 1.563; P = 0.031) and N2 disease (HR = 1.723; P = 0.012) were independent prognostic factors for poor survival. Conclusion: High levels of serum CRP and CEA, and N2 disease are independent prognostic indicators for the survival of patients with stage III-IV NSCLC. Key words: C-reactive protein, carcinoembryonic antigen, N2 disease, non-small cell lung cancer, survival analysis.

INTRODUCTION Correspondence: Dr Chang-Ping Wu MD, Department of Oncology, The Third Affiliated Hospital, Soochow University, Juqian Road 185, Changzhou 213003, Jiangsu Province, China. Email: [email protected] *These authors contributed equally to this work. Author contributions: Xue-Feng Ni and Ping Wu collection data and wrote the article; Chang-Ping Wu supervised the research. Conflict of interest: none Accepted for publication 28 April 2013.

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Non-small cell lung cancer (NSCLC) is the leading cancer-related cause of death worldwide.1 Locally advanced tumors represent more than 30% of cases at the time of diagnosis. NSCLC stages were recorded based on the American Joint Committee on Cancer staging system (7th edn).2 These tumors have a high risk of both local and systemic recurrence (80 and 60% of cases, respectively),3 justifying a therapeutic strategy


combining local and systemic treatment.4 The presence of mediastinal lymph node metastases (i.e. N2 disease) is associated with poor survival, mainly because of the high incidence of occult distant metastases. Survival rates of patients treated with surgery only or radiotherapy only range from 5 to 13% after 5 years.5,6 Several potential tumor markers have been examined, which are able to identify patients with an increased risk of recurrence and short overall survival (OS). One such potential marker is the carcinoembryonic antigen (CEA). CEA is a glycosylphosphatidylinositol cell surface anchored glycoprotein in which specialized sialofucosylated glycoforms serve as functional colon carcinoma L-selectin and E-selectin ligands, which may be critical to the metastatic dissemination of colon carcinoma cells.7–9 CEA is an acknowledged tumor marker in colorectal cancer and some have reported it to be a prognostic marker in lung cancer as well. The current evidence for the latter is, however, questionable. In NSCLC 18 studies10,11 reported statistically significant evidence for the use of CEA as a prognostic marker in NSCLC patients while seven studies12,13 were negative. Reliable prognostic tumor markers are required in order to select lung cancer patients who could benefit from more aggressive treatment.14 There have been numerous reports about the relationship between chronic inflammation and cancer. The inflammatory cells and cytokines found in tumors are highly likely to contribute to tumor growth progression and immune-suppression to combat an effective host anti-tumor response.15,16 Persistent infection of the host induces chronic inflammation and inflammatory cells induce DNA damage in proliferating cells by generating reactive oxygen and nitrogen species.15 C-reactive protein (CRP) is produced by hepatocytes that are regulated by interleukin (IL)-6.16,17 Several possible mechanisms have been postulated for the relationship between CRP and cancers. First, tumor growth can cause tissue inflammation, hence increasing the CRP level. Second, CRP could be an indicator of an immune response to tumor antigens. Third, cancer cells could increase the production of inflammatory cytokines, which could induce high concentrations of CRP in cancer patients.16 Preoperative elevation of serum CRP has been reported to be a prognostic indicator in esophageal, gastric, ovarian and colorectal carcinomas and in NSCLC.18–21 There have been few reports on late stage NSCLC. The purpose of our study was to identify serum biomarkers for late stage NSCLC. We measured the pretreat-

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X-F Ni et al.

ment serum levels of CRP as well as the relationship between serum CRP levels and other relevant variables such as sex, Eastern Cooperative Oncology Group (ECOG) status, smoking status, initial staging, N2 disease, albumin levels, white blood cell count, platelet (plt) count, CEA, comorbidity and pathology.

Patients’ characteristics Only patients with advanced or metastatic disease were included. A definitive histological analysis showed there were 18 patients with stage IIIA disease and nine patients with stage IIIB disease, 100 patients with stage IV disease (according to the American Joint Committee on Cancer Staging, 7th edn).2 There were 75 patients with malignant pleural metastasis or pericardial effusions according to the pathological diagnosis of malignant effusion. We reviewed patients who had histologically confirmed NSCLC at the Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu Province, China. The institutional review board approved the study. Informed consent was obtained from all patients before blood samples were obtained. A retrospective analysis was performed on initial CRP, sex, ECOG status, smoking status, initial staging, N2 disease, albumin levels, white blood cell count, plt count, CEA, comorbidity and pathology and survival. Patients with active concurrent infections were excluded. Comorbidity criteria included the following conditions: hypertension, diabetes mellitus, asthma and chronic obstructive lung disease. Pretreatment CRP values were measured from peripheral venous blood samples as part of the clinical routine, using an automatic nephelometer (Beckman Coulter Images, Fullerton, CA, USA), according to the manufacturer’s instructions. A normal serum level was defined as ≤10 mg/L as per the manufacturer’s manual. Thus, a serum CRP concentration greater than 10 mg/L was considered to represent a raised level. The CEA level of all serum samples was analyzed by chemiluminescence immunoassay (CEA Regent Kit, Abbott Diagnostics, Wiesbaden, Germany). Assays were carried out according to the manufacturer’s instructions using ARCHITECT i2000 SR (Abbott Laboratories). The normal CEA level was defined as ≤5 ng/mL.

Eligibility criteria Patients were recruited from January 2009 and February 2012. Eligibility criteria were: (i) cytologically or histologically proven NSCLC (adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma or large-

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cell carcinoma);22 (ii) American Joint Committee on Cancer (7th edn) stage IIIA, IIIB or IV tumor,2 after completion of a complete work-up that included a physical examination, imaging studies (thoracic computed tomography [CT]-scan, brain CT scan or magnetic resonance imaging, abdomen CT scan or ultrasound), fiberoptic bronchoscopy, ECT and mediastinoscopy. For those in whom the 18-fluorodeoxyglucose positron emission tomography (PET) scan showed increased uptake corresponding to N2 invasion, were also included. Endoscopic and endobronchial ultrasound were not available during the study period; (iii) the tumor could not be resectable at time of diagnosis, as evaluated by a multidisciplinary group of experienced surgeons, radiation and medical oncologists and pneumologists; and (iv) an ECOG performance status of 0–2.23

Imaging data All available CT scans were reviewed. Peripheral lung nodules were defined on CT scan as tumors with the center located in the outer third of the lung in either the sagittal or coronal plane. If CT images were not available a peripheral lesion was defined according to its relation to the pleural surface, as described in the pathology report. Mediastinal lymph nodes were considered to be positive by CT scan criteria when their short axis was 10 mm or more in size. In patients in whom PET scans were performed, reports were reviewed and considered positive if the metabolic activity in the mediastinum described exceeded background levels 1.5-fold.

Mediastinoscopy Cervical mediastinoscopy was performed in the standard fashion and selectively, determined by the presence of significant lymph nodes in the mediastinum observed on CT scan, by increased metabolic activity on PET or by surgeon’s preference. After the introduction of the mediastinoscope, biopsy specimens from stations 4R, 7 and 4 L were typically obtained. Biopsy specimens were also obtained from other stations when lymph nodes were encountered or specifically sought.

Malignant pleural effusion The diagnosis of malignant effusion was made when malignant cells were found on cytological examination or in a biopsy specimen. Patients with negative cytological findings were further examined with a closed pleural biopsy and those with negative findings on closed biopsy underwent video-assisted thoracoscopic surgery.

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Statistical analysis Results were given as means ± standard deviation or frequencies, according to type of parameter. The correlation between serum CRP level and other categorical clinical variables was analyzed using Pearson’s χ2 test. OS was measured from the date of diagnosis until the date of death or final follow up. Cumulative survival rates were determined using the Kaplan–Meier method, and the differences among groups were evaluated by the log–rank method. Patients lost to follow up were treated as censored data for the analysis of survival rates. A univariate Cox model with OS as the dependent variable was constructed and categorized with two factors levels as independent variables, and the factors that were significant in the univariate analysis were included in a multivariate Cox proportional hazards model for survival. Differences were considered significant at P < 0.05. All statistical calculations were performed using the Statistical Package for the Social Sciences, vers.13 (SPSS, Chicago, IL, USA).

RESULTS Clinical outcome A total of 127 NSCLC patients were included in the study. All patients were evaluable for analysis. The median follow-up period was 11.2 months (range, 0.5–44 months). Patients’ characteristics are summarized in Table 1. Their median age was 63 years (range, 31–81); 59 patients (47%) were male and most of them (n = 92; 72%) had good performance status (ECOG 0–1); 68 patients (54%) had no mediastinal lymph node involvement. In total, 27 patients (21%) had stage III and 100 (79%) had stage IV disease at the time of diagnosis; 24 patients (19%) had never smoked, and most had adenocarcinomas (n = 80; 63%).

Serum CRP and patient characteristics The initial CRP concentration in 72 patients (57%) was within the normal range, and it was elevated in 55 patients (43%). The mean value of serum CRP prior to treatment was 14.2 ± 16.7 mg/L; 3.8 ± 2.2 mg/L in the normal CRP group and 27.8 ± 17.6 mg/L in the high CRP group. Serum CRP level was significantly associated with plt count (P = 0.011).

Survival time Median survival time for all patients was 12 months (95% CI: 8.337–15.663). A significant association was

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Table 1

X-F Ni et al.

Baseline characteristics

Characteristics Age, median(range) 10 mg/L), hypoalbuminemia (albumin 5 ng/mL) and positive N2 disease were associated with shorter survival in univariate analysis. In multivariate analysis, only CRP, CEA and N2 disease were independent prognostic factors for survival of patients with NSCLC. Pathological N (pN) 2 NSCLC is heterogeneous, and many studies have evaluated the validity of various prognostic factors among pN2 NSCLC patients in order to develop a more accurate classification system.24–27 Long-term survival is strongly related to the local extension of the disease, ranging from 42 to 85% in the absence of lymph node metastases to 35–48% for N1 disease and 20–35% and 3–8%, respectively, for microscopic and clinical N2 disease.28–30 In patients with pN2 disease, a significant proportion of all cases of relapse

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Table 3 Multivariate analysis of factors associated with overall survival Factors CRP Normal High CEA Normal High Lymph node N2 Negative Positive Albumin Low Normal

Patients (n)

Hazard ratio (95% CI)


72 (57) 55 (43)

1 (ref.) 1.796 (1.190–2.711)


58 (46) 69 (54)

1 (ref.) 1.563 (1.041–2.346)


68 (54) 59 (47)

1 (ref.) 1.723 (1.126–2.635)


68 (54) 59 (47)

1 (ref.) 0.928 (0.531–1.622)


CEA, carcinoembryonic antigen; CRP, C-reactive protein; N2 disease, mediastinal lymph node metastasis.

is locoregional, varying between 20 and 40% in different studies.31–33 Patients with N2 disease had worse outcomes, largely due to higher relapse rates at distant sites. Currently, serum CEA is the most convenient as a potential prognostic biomarker in lung cancer. Numerous studies show that CEA is associated with a worse prognosis in advanced NSCLC.35,36 However, the use of several tumor markers when evaluating the patient’s prognosis and risk of recurrence might be a fruitful approach in planning the treatment of lung cancer patients in the future. This is substantiated by Tomita et al.’s findings;37 the simultaneous use of CYFRA21-1 and CEA levels may increase the power of prognostic value. Tailored treatment in advanced NSCLC is already feasible to some extent, based on histology, epidermal growth factor receptor (EGFR) mutation status and EML4-ALK mutation status,38 and this approach may be further refined in the future by the use of combinations of several biomarkers and mutation status. Chronic inflammation is associated with the risk of cancer. CRP is a commonly used marker of inflammation. We found high serum CRP in 43% of patients, suggesting that a large tumor burden is likely to increase inflammatory cytokines, such as IL-1, IL-2, tumor necrosis factor-α´ and interferon-γ,15,39 which stimulate CRP production.40 One possible mechanism is pulmonary infection (or obstructive pneumonia), which could increase white blood cell counts (WBC), subsequently increasing the pro-inflammatory cytokine CRP concentration. In the

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current study, therefore, we evaluated the correlation between WBC and CRP but failed to find any significant correlation (P = 0.414). The other possibility is that proinflammatory cytokines are produced by tumor necrosis or local tissue damage, which is caused by the tumor– host cell interaction. However, we are not certain whether those cytokines are produced directly by tumors. Our results support existing evidence that CRP is an independent prognostic indicator in late stage NSCLC. A number of theories have been proposed as to why an elevated serum CRP level should result in reduced survival. It has been suggested that the inflammatory response to tumor cells results in a tumor microenvironment rich in pro-inflammatory cytokines, lymphogenic or angiogenic factors and chemokines, creating conditions that favor tumor growth, angiogenesis and metastases.15,39,41 Therefore a high serum CRP may reflect a more aggressive tumor type. Alternatively, elevated CRP may demonstrate a non-specific inflammatory response stimulated by tissue necrosis or damage and therefore the high level reflects the tumor burden. For esophageal cancer, a correlation has been shown between elevated serum CRP concentration and malnutrition with impaired immunity.42 Patients with late stage NSCLC may be in poor nutritional condition. The presence of a systemic inflammatory response and an accompanying nutritional decline reduces patients’ tolerance to treatment toxicities and diminishes their compliance with treatment.43 Up to 27% of the patients who had an elevated serum CRP concentration in our study also had hypoalbuminemia. This is consistent with the observation that the development of hypoalbuminemia is often secondary to a systemic inflammatory response.44 However, in our study, hypoalbuminemia was not an independent prognostic factor in multivariate analysis. This study demonstrated that patients with high plt count have significantly higher levels of initial serum CRP (P = 0.011) than those with a normal plt count. About 90% of cancer patients with metastatic disease and half of patients with cancer have abnormal coagulation parameters.45 Tumor cells can produce procoagulant molecules that activate coagulation either directly or indirectly by initiating an inflammatory response. Oncogenic events in cancer cells (e.g. the expression of mutant K-ras, EGFR, phosphatase and tensin homolog lead to an increase in procoagulant molecule levels and activity, and thereby promote tumor aggressiveness, angiogenesis and hypercoagulability.46 Elevated plasma levels of d-dimer in patients with lung cancer are

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associated with decreased survival and a poor response to treatment. Pretreatment for the d-dimer level may be useful in predicting survival and response to treatment.47 In light of the close correlation between CRP and plt count, we suggest that inflammation and coagulation of NSCLC are two tightly linked processes. Patients with comorbidities (hypertension, diabetes mellitus, asthma and chronic obstructive lung disease) may have associated higher inflammation markers. In the current study, patients with a comorbidity constituted 29% of the total, but there was no relationship between comorbidity and CRP level (P = 0.241). Much larger prospective trials may be needed to evaluate this in the future. As for prognosis, elevated serum CRP was associated with reduced OS. This result suggests that it might be a useful marker to define a subset of patients with bad prognosis who require intensive treatment. For example, patients with higher CRP pretreatment in the same stage may require more enhanced systemic chemotherapy than the lower CRP group. It is very possible that pretreatment serum CRP was not sufficient for predicting the chemo-response. Therefore, it is better to monitor serial serum CRP levels, including not only pretreatment but also during and after treatment, since chemo-sensitive tumors might result in tumor necrosis, thereby inducing an acute phase reaction. Lack of records of the use of non-steroidal antiinflammatory drugs is another shortcoming of our study. A drug history can help to evaluate the potential impact of their use. We also need more cases to analyze the effect of various chemotherapies and target therapies on markers. A single nucleotide polymorphism at some positions of the CRP gene was reported to be a determinant of cancer risk. We wish to perform CRP genotype testing in the future to explore its association with carcinogenesis.48,49 Our study has demonstrated the link between raised CRP and the malignant potential of late stage NSCLC. Combining CRP and CEA and N2 disease may enhance the power to predict the prognosis of NSCLC and may provide a useful, simple and reproducible clinical tool. The relationship also highlights potential novel therapeutic targets. However, further investigations are needed because of the limitations of a study with a small sample size.

Conclusions The aim of this study was to clarify the roles of CRP, CEA and N2 disease in late stage NSCLC. In our study,

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a positive correlation between CRP and the plt count was observed. In summary, increasing CRP values and CEA were independent prognostic factors of NSCLC, associated with poorer survival; the same was true of N2 metastases. Pretreatment serum levels of CRP and CEA are easily measurable biomarkers of prognostic significance in NSCLC. They can be used in combination with conventional staging to predict survival in patients with NSCLC. These prognostic markers could improve patient selection for various treatment strategies in the future. It is hypothesized that the systemic inflammatory response is closely related to the chance of tumor dissemination.

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Elevated serum C-reactive protein, carcinoembryonic antigen and N2 disease are poor prognostic indicators in non-small cell lung cancer.

To assess the prognostic value of mediastinal lymph node metastases (N2 disease), carcinoembryonic antigen (CEA) levels and C-reactive protein (CRP) i...
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