Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: An analysis of Japan Multinational Trial Organisation LC00-03

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Abstract

We examined the impact of pretreatment neutrophil count on survival in patients with advanced non-small-cell lung cancer (NSCLC). A total of 388 chemo-naïve patients with stage IIIB or IV NSCLC from a randomised controlled trial were evaluated. The effects of pretreatment peripheral blood neutrophil, lymphocyte and monocyte counts and neutrophil–lymphocyte ratio on survival were examined using the proportional hazards regression model to estimate hazard ratios after adjustment for covariates. The optimal cut-off value was determined by proportional hazards regression analysis with the minimum P-value approach and shrinkage procedure. After adjustment for prognostic factors, the pretreatment elevated neutrophil count was statistically significantly associated with short overall (P = 0.0008) and progression-free survival (P = 0.024), whereas no association was found between prognosis and lymphocyte or monocyte count. The cut-off value selected for neutrophil count was 4500 mm–3 (corrected hazard ratio, 1.67; 95% confidence interval (CI), 1.09–2.54). The median survival time was 19.3 months (95%CI, 16.5–21.4) for the low-neutrophil group (⩾4500 mm–3, n = 204) and was 10.2 months (95%CI, 8.0–12.3) for the high-neutrophil group (⩾4500 mm–3, n = 184). We confirmed that pretreatment elevated neutrophil count is an independent prognostic factor in patients with advanced NSCLC receiving modern chemotherapy. Neutrophil count is easily measured at low cost, and it may be a useful indicator of patient prognosis.

Introduction

The prognosis for patients with advanced non-small-cell lung cancer (NSCLC) (TNM stage IIIB with a positive pleural effusion, or stage IV) has improved with recent advances in systemic chemotherapy, but still remains poor, with a median overall survival time between 4 and 15 months.1 Prognostic factors identified in previous studies include tumour stage, performance status (PS), weight loss, sex, plasma lactate dehydrogenase (LDH) level and the presence of bone, liver or skin metastases.2 Although novel immunological and histological biomarkers have been identified, these are often time-consuming to measure, and this is not part of the standard practice.

It is now evident that inflammatory cells in the tumour microenvironment have significant effects on tumour development.3, 4, 5, 6 Elevation in the pretreatment neutrophil count has been proposed as a prognostic factor for poor survival in patients with metastatic renal cell carcinoma,7, 8, 9 and elevated neutrophil, monocyte or leucocyte count has been associated with poor survival in patients with metastatic melanoma.10, 11 A high-neutrophil–lymphocyte ratio may be related to poor prognosis in patients with colorectal cancer12 and in those with advanced gastric cancer.13 The European Lung Cancer Working Group found that the high-neutrophil count was an independent prognostic factor for poor survival in patients with unresectable advanced NSCLC14 and in those with small-cell lung cancer.15 A retrospective study found that neutrophil count was of prognostic value in patients with lung cancer.16

The aim of this study was to examine and confirm the impact of pretreatment peripheral blood neutrophil, monocyte and lymphocyte counts on overall and progression-free survival in a well-defined population of patients with advanced NSCLC being treated with regimens using newer chemotherapeutic agents in a randomised controlled clinical trial.

Section snippets

Study population

A total of 401 chemo-naïve NSCLC patients with stage IIIB with pleural effusion or stage IV without brain metastasis, who had Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1, were enrolled from 45 institutions in Japan between March 2001 and April 2005 into Japan Multinational Trial Organisation LC00-0317 (registered with ClinicalTrials.gov identifier NCT00079287). Patients underwent one of two treatment regimens: intravenous vinorelbine (25 mg/m2) plus gemcitabine (1000 mg/m2) on days 1

Patients’ characteristics

Of 388 patients, 276 patients had died, and the median follow-up time for the 112 surviving patients was 567 d (range: 70–1711 d). The characteristics of the 388 patients (276 men [71%], 112 women [29%], median age 65 years [range, 33–81 years]) included in the present study are shown in Table 1. Median pretreatment counts of neutrophils, lymphocytes and monocytes were 4304 mm–3, 1386 mm–3 and 404.2 mm–3, respectively. Spearman’s rank correlations were 0.351 for neutrophils and monocytes, 0.034 for

Discussion

In multivariate analysis after adjustment for known prognostic factors, we found linear associations between pretreatment elevated neutrophil count and short overall and progression-free survival. As there was no such association for the lymphocyte count, the relationship between neutrophil-lymphocyte ratio and overall survival was also found, however, it was to some degree weak and non-linear. As a consequence, we consider that absolute neutrophil count may better serve as a prognostic factor.

Conclusion

Using the dataset from a randomised controlled trial, we have confirmed that pretreatment peripheral blood neutrophil count is an independent prognostic factor in patients with advanced NSCLC receiving modern chemotherapy. The results need to be investigated for generalisability in other populations. Since neutrophil count is easily measured at low cost, it may be a useful predictor of prognosis in clinical practice. Considering the strength of the association reported here, neutrophil count

Conflict of interest statement

Kaoru Kubota has received honoraria from Eli Lilly, Sanofi-Aventis, and Chugai. All other authors declared no conflicts of interest.

Acknowledgements

This study was sponsored by the Japan Multinational Trial Organisation. We thank the Translational Research Informatics Centre, Kobe, Japan, for data management.

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