HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Elizabeth Belcher Peter Goldstraw Eric Lim Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sarraf, K. M. Articles by Lim, E. Search for Related Content PubMed Articles by Sarraf, K. M. Articles by Lim, E. Related Collections Lung - cancer

J Thorac Cardiovasc Surg 2009;137:425-428
© 2009 The American Association for Thoracic Surgery

General Thoracic Surgery

Neutrophil/lymphocyte ratio and its association with survival after complete resection in non–small cell lung cancer

^a Academic Division of Thoracic Surgery, Royal Brompton Hospital, London, United Kingdom
^b Department of Histopathology, Royal Brompton Hospital, London, United Kingdom

Received for publication February 22, 2008; revisions received April 16, 2008; accepted for publication May 15, 2008.

^_* Address for reprints: Eric Lim, FRCS (C-Th), Academic Division of Thoracic Surgery, Royal Brompton Hospital, Sydney St, London SW3 6NP, United Kingdom. (Email: e.lim{at}rbht.nhs.uk).

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
Objective: Increasing neutrophil/lymphocyte ratios on preoperative blood tests have been associated with worse survival after resection of colorectal cancer. We sought to determine factors associated with increasing neutrophil/lymphocyte ratios and the stage-adjusted prognostic effect in patients undergoing resection for non–small cell lung cancer.

Methods: We performed a retrospective review of patients undergoing complete resection for non–small cell lung cancer between 1999 and 2005. Data acquisition was through patient medical records, blood results recorded on admission before surgical intervention, and follow-up by National Health Service database searches and hospital records. Cox proportional hazards regression was used to estimate the effect of neutrophil/lymphocyte ratio on stage-adjusted survival.

Results: During the study period, 178 patients underwent pulmonary resection. Of 177 patients, the majority were male 104 (59%), with a mean age of 63 years (standard deviation, 10 years). The median follow-up time was 29 months (interquartile range, 8–56 months), and overall survival was 83% and 54% at 1 and 5 years, respectively. Higher stage was the only factor found to be associated with increasing neutrophil/lymphocyte ratios (P = .019). Total white cell count (P = .990) and neutrophil count (P = .490), age (P = .290), and cell type (P = .490) were not significant predictors of mortality. On multivariable analysis after adjusting for stage, increasing neutrophil/lymphocyte ratios (hazard ratio, 1.10; 95% confidence interval, 1.03–1.17; P = .004) remained an independent prognostic indicator.

Conclusions: Increasing preoperative neutrophil/lymphocyte ratios are associated with higher stage but remain an independent predictor of survival after complete resection for primary lung cancer and are a potential biomarker to stratify high risk of death in patients with stage I disease.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
Currently, joint guidelines issued by Cancer Care Ontario and the American Society of Clinical Oncology do not recommend the use of adjuvant chemotherapy in patients with completely resected stage I lung cancer.¹ Uniformly good survival in patients with stage I disease is not always the case because sophisticated, expensive, and not widely available techniques, such as tumor gene expression profiling, are able to substratify patients with early-stage cancer into high- and low-risk subsets.²

The purpose of this study was to determine the factors associated with increasing neutrophil/lymphocyte ratios (NLRs) and the relationship to survival in patients with non–small cell lung cancer to evaluate the discriminating value of the NLR to stratify patients with stage I disease at high risk of death.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
The chairman of the ethics committee approved this study and waived the need for ethics review. This study was conducted on patients operated on by a single surgeon (PG) between 1999 and 2005 and included all patients with non–small cell lung cancer who had undergone complete resection. We excluded any patients with coexistent hematologic disorders or known active infection at the time of surgical intervention to ensure that the white cell count was representative of a normal baseline value.

Data Acquisition
Data were compiled from individual patient medical case notes, electronic patient records (for laboratory results), and pathology reports. Demographics and serum values for the NLR were measured on the day before the operation to ascertain the baseline values for neutrophil and lymphocyte counts. Survival status was determined from the date of last follow-up in a hospital outpatient clinic or general practitioner clinic. Mortality status was documented from patient records and the National Health Service (United Kingdom) strategic tracing service.

Statistical Analysis
Categorical data are presented as frequencies (percentages) and continuous data as means with standard deviations or medians with interquartile ranges. Regression analysis was used to ascertain factors associated with increasing NLRs, and logarithmic transformation of the NLR was required to satisfy distributional assumption required for linear regression.

Receiver operating characteristic plots were constructed in the stage I subset of patients to determine the joint maximum sensitivity and specificity of a threshold value to stratify patients at high risk of death.

Actuarial survival was estimated by using the Kaplan–Meier method, and differences were tested with the log-rank test. Increasing values of NLR were expressed in tertiles to retain sufficient numbers per group for comparison. Cox proportional hazards regression was used to ascertain the individual contribution of factors associated with survival and to compare the stage-adjusted survival. Statistical analyses were performed with Stata version 9.2 (StataCorp, College Station, Texas) and R version 2.4.1 (R Core Development Team, Vienna, Austria).³

	Results

Top Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
From January 1, 1999, to December 31, 2005, a total of 178 patients underwent surgical resection for non–small cell lung cancer. We excluded 1 patient with leukemia, leaving 177 suitable for inclusion. Systematic nodal dissection was undertaken in all cases. The mean age of the cohort was 63 years (standard deviation, 10 years), and 104 (59%) were men. The baseline characteristics, extent of operation, and pathologic stage are presented in Table 1 . Follow-up was complete, with a median time to follow-up of 29 months (interquartile range, 8–56 months) and a 1- and 5-year overall survival of 83% and 54%, respectively.

Predictors of Survival
On univariable Cox regression modeling, neither total white cell count (P = .990) nor neutrophil count (P = .490) was significantly associated with risk of death. Increasing lymphocyte count was observed to be associated with a lower hazard ratio for death at 0.62 (P = .012), and increasing NLRs were observed to be associated with an increasing hazard ratio of death at 1.10 (P = .001, Figure 1 ). Hazard ratios of the covariates explored on univariable analysis are presented in Table 2 .

View larger version (10K): [in this window] [in a new window]   Figure 1. Survival by neutrophil/lymphocyte ratio tertiles.

View larger version (16K): [in this window] [in a new window]   Figure 2. Survival of 83 patients with pathologic stage I disease. NLR, Neutrophil/lymphocyte ratio; ROC, receiver operating characteristic.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion Conclusions References

The NLR, an inexpensive, reproducible, and widely available blood test, has been found to be an important indicator of adverse prognosis in colorectal^4,5 and gastric⁶ cancers. Although the cause for the association between increasing NLRs and adverse outcome has not been elucidated, individually, a high neutrophil count has been reported as an adverse marker of prognosis in metastatic melanoma⁷ and renal cell carcinoma,⁸ and a low lymphocyte count has been reported as a marker of mortality in pancreatic cancer.⁹

Recently, an increasing neutrophil count has also been identified as an independent predictor of death in patients with advanced non–small cell lung cancer,¹⁰ and neutrophils have been implicated in the promotion of aerogenous metastasis in patients with bronchioloalveolar carcinoma.¹¹ On its own, as an isolated measured variable, we did not find any association between the absolute value of the neutrophil count on survival after complete resection of early-stage non–small cell lung cancer; in part this might be due to statistical variation or simply the lack of a consistent relationship.

A low lymphocyte count is a recognized predictor of poor survival in patients with advanced cancer attributed to the fundamental role of lymphocytes in cell-mediated immunity with destruction of host cancer cells and has been found to be a predictive marker of response to chemotherapy.¹² Our results are consistent in this cohort of patients with early-stage lung cancer, even after complete resection, because higher preoperative lymphocyte counts were found to be associated with improved survival. It is plausible that host cell-mediated immunity continues to exert important effects on destruction of any residual tumor cells and micrometastases, despite complete resection of the main tumor. It will require a study of relapse patterns to assess the possible implications and mechanisms of NLRs.

In small cell lung carcinoma, after complete resection, high lymphocyte counts have been associated with improved survival, which is ascribed to the pivotal role of specific T-cell subsets (including tumor-infiltrating lymphocytes) in cytotoxic cell death and cytokine production that regulates proliferation and metastatic activity of tumor cells.¹³

The NLR, as a measure of the relative differences of the baseline neutrophil and lymphocyte counts, was discovered to be a more powerful predictor of death than either component alone or pathologic stage. On regression analysis, we demonstrated the association between stage and increased NLR (P = .019). However, it is not possible to distinguish cause from effect, increasing tumor burden might incite a neutrophil reaction, and certainly an association was also present between increasing absolute neutrophil counts and increasing pathologic stage (P = .017). Multivariable modeling, however, confirmed a more independent (and more powerful) effect than pathologic stage as a biomarker of poor prognosis. This has also been recently reported in advanced lung cancer, where a similar association was observed. The index was presented as a reversed ratio (lymphocyte/neutrophil ratio), and lower scores were identified as an increasing independent predictor of death.¹⁴

Currently, joint guidelines issued by Cancer Care Ontario and the American Society of Clinical Oncology do not recommend the use of adjuvant chemotherapy in patients with completely resected stage I lung cancer,¹ citing little evidence of efficacy in these subgroups. The NLR is a potential biomarker to influence patient selection in this regard because it is almost universally available and adds no additional cost to routine preoperative workup in comparison with more sophisticated and expensive technologies.² Clearly further validation work and a feasibility study are required before it can be considered for clinical use.

	Conclusions

Top Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
Increasing preoperative NLRs are associated with higher stage but remain an independent predictor of survival after complete resection for non–small cell lung cancer and are a potential biomarker to stratify high risk of death in patients with stage I disease.

	References

Top Abstract Introduction Materials and Methods Results Discussion Conclusions References

 

1. Pisters KM, Evans WK, Azzoli CG, et al. Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline. J Clin Oncol 2007;25:5506-5518.[Abstract/Free Full Text]
   
2. Potti A, Mukherjee S, Petersen R, et al. A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 2006;355:570-580.[Medline]
   
3. R Development Core Team (2006). R: a language and environment for statistical computing. Available at: http://www.R-project.org. Accessed August 1, 2008.
   
4. Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ. Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 2005;91:181-184.[Medline]
   
5. Halazun KJ, Aldoori A, Malik HZ, et al. Elevated preoperative neutrophil to lymphocyte ratio predicts survival following hepatic resection for colorectal liver metastases. Eur J Surg Oncol 2008;34:55-60.[Medline]
   
6. Hirashima M, Higuchi S, Sakamoto K, Nishiyama T, Okada H. The ratio of neutrophils to lymphocytes and the phenotypes of neutrophils in patients with early gastric cancer. J Cancer Res Clin Oncol 1998;124:329-334.[Medline]
   
7. Schmidt H, Bastholt L, Geertsen P, et al. Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model. Br J Cancer 2005;93:273-278.[Medline]
   
8. Atzpodien J, Royston P, Wandert T, Reitz M. Metastatic renal carcinoma comprehensive prognostic system. Br J Cancer 2003;88:348-353.[Medline]
   
9. Fogar P, Sperti C, Basso D, et al. Decreased total lymphocyte counts in pancreatic cancer: an index of adverse outcome. Pancreas 2006;32:22-28.[Medline]
   
10. Paesmans M, Sculier JP, Libert P, et al. Prognostic factors for survival in advanced non-small-cell lung cancer: univariate and multivariate analyses including recursive partitioning and amalgamation algorithms in 1,052 patients. The European Lung Cancer Working Party. J Clin Oncol 1995;13:1221-1230.[Abstract]
    
11. Wislez M, Antoine M, Rabbe N, et al. Neutrophils promote aerogenous spread of lung adenocarcinoma with bronchioloalveolar carcinoma features. Clin Cancer Res 2007;13:3518-3527.[Abstract/Free Full Text]
    
12. Lissoni P, Brivio F, Fumagalli L, et al. Efficacy of cancer chemotherapy in relation to the pretreatment number of lymphocytes in patients with metastatic solid tumors. Int J Biol Marker 2004;19:135-140.
    
13. Eerola AK, Soini Y, Paakko P. A high number of tumor-infiltrating lymphocytes are associated with a small tumor size, low tumor stage, and a favorable prognosis in operated small cell lung carcinoma. Clin Cancer Res 2000;6:1875-1881.[Abstract/Free Full Text]
    
14. Nakahara Y, Mochiduki Y, Miyamoto Y, Nakahara Y, Katsura Y. Prognostic significance of the lymphocyte-to-neutrophil ratio in percutaneous fine-needle aspiration biopsy specimens of advanced nonsmall cell lung carcinoma. Cancer 2005;104:1271-1280.[Medline]
    

This article has been cited by other articles:

				M. TOMITA, T. SHIMIZU, T. AYABE, A. YONEI, and T. ONITSUKA Preoperative Neutrophil to Lymphocyte Ratio as a Prognostic Predictor after Curative Resection for Non-small Cell Lung Cancer Anticancer Res, September 1, 2011; 31(9): 2995 - 2998. [Abstract] [Full Text] [PDF]

				K. Suzuki, S. S. Kachala, K. Kadota, R. Shen, Q. Mo, D. G. Beer, V. W. Rusch, W. D. Travis, and P. S. Adusumilli Prognostic Immune Markers in Non-Small Cell Lung Cancer Clin. Cancer Res., August 15, 2011; 17(16): 5247 - 5256. [Abstract] [Full Text] [PDF]

				H. Bhutta, R. Agha, J. Wong, T. Y. Tang, Y. G. Wilson, and S. R. Walsh Neutrophil-Lymphocyte Ratio Predicts Medium-Term Survival Following Elective Major Vascular Surgery: A Cross-Sectional Study Vascular and Endovascular Surgery, April 1, 2011; 45(3): 227 - 231. [Abstract] [PDF]

				S. C. H. Kao, N. Pavlakis, R. Harvie, J. L. Vardy, M. J. Boyer, N. van Zandwijk, and S. J. Clarke High Blood Neutrophil-to-Lymphocyte Ratio Is an Indicator of Poor Prognosis in Malignant Mesothelioma Patients Undergoing Systemic Therapy Clin. Cancer Res., December 1, 2010; 16(23): 5805 - 5813. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Elizabeth Belcher Peter Goldstraw Eric Lim Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sarraf, K. M. Articles by Lim, E. Search for Related Content PubMed Articles by Sarraf, K. M. Articles by Lim, E. Related Collections Lung - cancer