Journal Information
Download PDF
More article options
Letter to the Editor
DOI: 10.1016/j.pulmoe.2019.02.007
Open Access
Available online 30 March 2019
Inflammatory prognostic biomarkers in advanced non-small cell lung cancer
D. Machadoa,
Corresponding author

Corresponding author.
, C. Marquesa, M. Diasb, S. Campainhab, A. Barrosob
a Pulmonology Department, Gaia/Espinho Hospital Center, Vila Nova de Gaia, Portugal
b Thoracic Tumors Multidisciplinary Unit, Pulmonology Department, Gaia/Espinho Hospital Center, Vila Nova de Gaia, Portugal
This item has received

Under a Creative Commons license
Article information
Full Text
Download PDF
Figures (1)
Tables (2)
Table 1. Clinicopathological features at diagnosis.
Table 2. Prognostic factors for overall survival estimated by univariate and multivariate Cox regression analyses.
Show moreShow less
Full Text
Dear Editor,
NOTICE Undefined index: abbrev (includes_ws_v2/librerias/html/item.php[401])

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all cases of lung cancer. In spite of the progress achieved in treatments, patients with advanced disease still have a poor prognosis. Prognostic evaluation in cancer is a challenging process. Features such as age, gender, histopathology and stage are known prognostic factors, but are not enough to explain the global prognosis.1 Therefore, new prognostic markers are needed. The use of biological markers easily collected through a simple method like a peripheral blood sample is appealing. The ideal biomarker should have a long half-life, be measured precisely by an inexpensive and simple test, and be sensitive to change so that it can be followed over time. C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) meet these criteria and elevated levels of these biomarkers have been linked to poor prognosis in several cancers.2

The aim of this work was to evaluate the relationship between CRP and NLR values at the time of diagnosis and the overall survival (OS) in patients with NSCLC at stages IIIB and IV.

We performed a retrospective study that included patients diagnosed with NSCLC at stages IIIB and IV (based on the tumor-node-metastasis classification, 7th edition) between January 2012 and March 2016, who were treated with palliative systemic therapy. Patients with clinical evidence of infection at the time of diagnosis were excluded since infection is a non-cancer inflammatory marker-modifying factor. CRP and NLR values at the time of diagnosis and other clinical variables were retrieved from patients’ medical records. The NLR ratio was calculated dividing the absolute neutrophil count by the absolute lymphocyte count. In accordance to previous studies,3,4 a cut-off value of 3.5 was evaluated as a potential prognostic biomarker. The cut-off value of CRP varies among different studies, but a systematic review verified that 10mg/L was the most frequently selected.2 Accordingly, we adopted this value as cut-off.

Kaplan–Meier analysis with log-rank test was performed to calculate median OS. Univariate and multivariate analyses for OS were performed using the Cox proportional hazards model and was expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). A p-value <0.05 was considered statistically significant. Statistical analyses were performed using SPSS® for Windows® (version 24.0, Chicago, Illinois).

Patient characteristics are shown in Table 1. From a total of 569 patients diagnosed with NSCLC, 318 fulfilled the required criteria, 262 (82.4%) of which at stage IV. Most patients had increased values of CRP (60.1%) or NLR (56.6%) at the time of diagnosis. Male gender, loss of 5% or more of body weight before diagnosis, an Eastern Cooperative Oncology Group (ECOG)2, NRL>3.5 and CRP>10mg/L were significantly associated with worse OS (Table 2). NLR and CRP were independent prognostic factors for OS when adjusted by the other clinical factors. Patients with NLR>3.5 had increased risk of death (HR 1.350; 95% CI 1.036–1.760; p=0.026). The same was verified with CRP, with values >10mg/L predicting worse survival (HR 1.462; 95% CI 1.113–1.920; p=0.006). Among the other clinical variables, ECOG2 and male gender also independently predicted worse survival. The two biomarkers were then combined to obtain four subgroups: group A with decreased values of both markers (67 patients), group B with CRP10mg/L and NLR>3.5 (60 patients), group C with CRP>10mg/L and NLR3.5 (71 patients), and group D with both markers increased (120 patients). Patients from group A had a median survival of 24 months, significantly higher than those with at least one increased biomarker (p<0.001). Patients from groups B, C and D had similar median survival times (5, 7 and 5 months, respectively, p>0.05) (Fig. 1).

Table 1.

Clinicopathological features at diagnosis.

Characteristics at diagnosisNumber of patients (%)a 
Age (years)70±12 
GenderFemale  76 (23.9) 
Male  242 (76.1) 
Performance statusECOG 0  41 (12.9) 
ECOG 1  193 (60.7) 
ECOG 2  58 (18.2) 
ECOG 3  19 (6) 
ECOG 4  7 (2.2) 
Weight loss<5%  122 (38.4) 
5–10%  124 (39) 
>10%  72 (22.6) 
Smoking statusNever smoker  78 (24.5) 
Ex-smoker  118 (37.1) 
Current smoker  122 (38.4) 
HistopathologyAdenocarcinoma  215 (67.6) 
Squamous cell carcinoma  67 (21.1) 
Others  36 (11.3) 
TNM stagingIIIB  56 (17.6) 
IV  262 (82.4) 
NLR≤3.5  138 (43.4) 
>3.5  180 (56.6) 
CRP≤10mg/L  127 (39.9) 
>10mg/L  191 (60.1) 

Age is displayed as mean±standard deviation.

CRP – C-reactive protein; ECOG – Eastern Cooperative Oncology Group; NLR – neutrophil–lymphocyte ratio; TNM – tumor-node-metastasis.

Table 2.

Prognostic factors for overall survival estimated by univariate and multivariate Cox regression analyses.

Characteristics  Univariate analysisMultivariate analysis
  HR  95% CI  p-value  HR  95% CI  p-value 
Male gender  1.553  1.146–2.105  0.003  1.408  1.032–1.921  0.031 
Ever smoker  1.150  0.866–1.528  0.335       
ECOG1.897  1.451–2.480  <0.001  1.711  1.289–2.272  <0.001 
Weight loss5%  1.348  1.043–1.741  0.022       
NSCLC other than adenocarcinoma  1.211  0.934–1.571  0.148       
NLR>3.5  1.694  1.315–2.183  <0.001  1.350  1.036–1.760  0.026 
CRP>10mg/L  1.766  1.361–2.291  <0.001  1.462  1.113–1.920  0.006 

CRP – C-reactive protein; ECOG – Eastern Cooperative Oncology Group; HR – hazard ratio; NLR – neutrophil–lymphocyte ratio; NSCLC – non-small cell lung cancer.

Statistically significant values are in bold.

Figure 1.

Overall survival according to biomarkers groups. (A) CRP10mg/L and NRL3.5. (B) CRP10mg/L and NLR>3.5. (C) CRP>10mg/L and NRL3.5. (D) CRP>10mg/L and NRL>3.5.


Several studies have demonstrated a relationship between CRP and NLR values and survival in cancer patients.2,3 It has been reported that inflammation could facilitate cancer development and is associated with a worse outcome.5 Systemic inflammation can be accessed by NLR and CRP blood levels, two minimally invasive and inexpensive biomarkers.2

We observed that the presence of NRL>3.5 or CRP>10mg/L was independently associated with shorter OS. We found no cumulative effect on OS when both biomarkers are increased. Besides, each of these markers increases the hazard of death in the same magnitude. Our results suggest that it is the presence of inflammation in lung cancer that is associated with worse prognosis, rather than the marker chosen for its evaluation. Cancer-related inflammation affects many aspects of cancer including proliferation and survival of tumor cells, angiogenesis, metastization and tumor response to therapy.6 Previous studies have also evaluated this association between increased inflammation and worse survival in lung cancer. As in ours, the majority have identified increased values of NLR or CRP to be associated with worse OS.1,2,7

These results highlight the importance of routinely assessing the presence of systemic inflammation as a part of the global approach of patients with lung cancer.

We recognize some limitations in our study. First, it is a retrospective and single center study, with inherent selection bias. Second, although patients with evidence of infection were excluded, we cannot ensure that other non-cancer CRP and NLR modifying factors were present. Third, mutational status and treatment regimens were not reported and may have influenced results.

In conclusion, the results of this study demonstrated that CRP and NLR are independent prognostic factors for advanced stage NSCLC patients, but additional studies are necessary to assess if long term monitoring of these biomarkers will be helpful in outcomes evaluation.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest

Dr. Barroso reports personal fees from AstraZeneca, Boehringer Ingelheim, Lda, Eli Lilly and Company, Pierre Fabre Portugal, Roche Farmacêutica Química, Lda, Merck and Bristol-Myers Squibb, outside the submitted work. The other authors have no conflicts of interest to declare.



N. Dirican, A. Dirican, C. Anar, S. Atalay, O. Ozturk, A. Bircan, et al.
A new inflammatory prognostic index based on C-reactive protein, the neutrophil to lymphocyte ratio and serum albumin is useful for predicting prognosis in non-small cell lung cancer cases.
Asian Pac J Cancer Prev, 17 (2016), pp. 5101-5106
S. Shrotriya, D. Walsh, N. Bennani-Baiti, S. Thomas, C. Lorton.
C-reactive protein is an important biomarker for prognosis tumor recurrence and treatment response in adult solid tumors: a systematic review.
PLoS ONE, 10 (2015), pp. e0143080
B.A. Derman, J.N. Macklis, M.S. Azeem, S. Sayidine, S. Basu, M. Batus, et al.
Relationships between longitudinal neutrophil to lymphocyte ratios, body weight changes, and overall survival in patients with non-small cell lung cancer.
BMC Cancer, 17 (2017), pp. 141
P. Forget, C. Khalifa, J.P. Defour, D. Latinne, M.C. Van Pel, M. De Kock.
What is the normal value of the neutrophil-to-lymphocyte ratio?.
BMC Res Notes, 10 (2017), pp. 12
F. Zhang, L. Ying, J. Jin, K. Chen, N. Zhang, J. Wu, et al.
The C-reactive protein/albumin ratio predicts long-term outcomes of patients with operable non-small cell lung cancer.
Oncotarget, 8 (2017), pp. 8835-8842
M. Gomes, A.L. Teixeira, A. Coelho, A. Araújo, R. Medeiros.
The role of inflammation in lung cancer.
Adv Exp Med Biol, 816 (2014), pp. 1-23
X. Jing, C. Huang, H. Zhou, C. Li, L. Fan, J. Chen, et al.
Association between serum C-reactive protein value and prognosis of patients with non-small cell lung cancer: a meta-analysis.
Int J Clin Exp Med, 8 (2015), pp. 10633-10639

Subscribe to our newsletter

Article options

Are you a health professional able to prescribe or dispense drugs?

Cookies policy
To improve our services and products, we use cookies (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here.