The systemic inflammation-based neutrophil–lymphocyte ratio: Experience in patients with cancer

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Abstract

There is increasing and consistent evidence that cancer-associated inflammation is a key determinant of outcome in patients with cancer. Various markers of inflammation have been examined over the past decade in an attempt to refine stratification of patients to treatment and predict survival. One routinely available marker of the systemic inflammatory response is the neutrophil–lymphocyte ratio (NLR), which is derived from the absolute neutrophil and absolute lymphocyte counts of a full blood count. To date, over 60 studies (>37,000 patients) have examined the clinical utility of the NLR to predict patient outcomes in a variety of cancers. The present systematic review examines and comments on the clinical utility of the NLR. The NLR had independent prognostic value in (a) unselected cohorts (1 study of >12,000 patients), (b) operable disease (20 studies, >4000 patients), (c) patients receiving neoadjuvant treatment and resection (5 studies, >1000 patients), (d) patients receiving chemo/radiotherapy (12 studies, >2000 patients) and (e) patients with inoperable disease (6 studies, >1200 patients). These studies originated from ten different countries, in particular UK, Japan, and China. Further, correlative studies (15 studies, >8500 patients) have shown that NLR is elevated in patients with more advanced or aggressive disease evidenced by increased tumour stage, nodal stage, number of metastatic lesions and as such these patients may represent a particularly high-risk patient population. Further studies investigating the tumour and host-derived factors regulating the systemic inflammatory response, in particular the NLR, may identify novel treatment strategies for patients with cancer.

Introduction

Cancer is the leading cause of disease worldwide with 12.7 million new cancer cases diagnosed worldwide in 2008 [1]. More than one in three people will develop some form of cancer in their lifetime and it remains the leading cause of death with 7.6 million cancer deaths worldwide recorded in 2008 [1], far exceeding deaths from other diseases such as heart disease and stroke [1]. Despite intense research activity outcomes from malignancy remain poor for the most common cancers.

In recent years there have been significant advances in cancer treatment. However, the appropriate stratification of cancer patients and subsequent allocation to surgical, oncological and palliative treatments remains a challenge. Until recently, the prediction of outcome has relied almost exclusively on accurate staging of the tumour. Indeed, many studies have attempted to refine TNM staging using tumour-associated criteria.

It is now widely recognised that outcomes in patients with cancer are not determined by tumour characteristics alone, and that patient-related factors are also key to outcome. In the last decade, it has become increasingly apparent that cancer-associated inflammation is a key determinant of disease progression and survival in most cancers [2], [3]. In particular, the host response in the form of systemic inflammation has been shown to independently predict outcome. The basis of this is not altogether clear, however a marked systemic inflammatory response is associated with important patient-related factors such as nutritional, functional and immunological decline.

In recent years many studies have investigated the most commonly used measures of the systemic inflammatory response and their potential use in stratifying cancer patients.

For example, there is good evidence that markers of the acute phase response, particularly C-reactive protein and albumin, are both sensitive and reliable markers of systemic inflammation in cancer patients [4]. Indeed, the last decade has seen the evolution of a prognostic scoring system, the Glasgow Prognostic Score (GPS) based on the combination of these acute phase proteins that provides objective, reliable prognostic information for both operable and inoperable cancers [5]. Indeed, this scoring system has been validated in a variety of clinical scenarios and is now recognised to have prognostic value, independent of tumour-based factors [5].

It is also well established that the systemic inflammatory response is associated with alterations in circulating white blood cells, specifically the presence of neutrophilia with a relative lymphocytopaenia [6], [7]. In addition, haematological tests are carried out routinely for cancer patients in a variety of clinical scenarios, and as such represent an easily measurable objective parameter able to express the severity of the systemic inflammatory response in patients with cancer. Indeed, Walsh et al., investigated the prognostic value of the neutrophil–lymphocyte ratio (NLR), in their centre, because C-reactive protein concentrations were not routinely performed as part of pre-treatment assessment [8].

In recent years, and in a similar way to the GPS [5], many research groups have investigated the value of the haematological components of the systemic inflammatory response specifically for use in predicting outcome, and have reported that the individual components of the differential white cell count, specifically the neutrophil and lymphocyte counts, may have clinical utility in predicting survival [9]. Indeed, the combination of these haematological components of the systemic inflammatory response, as the neutrophil–lymphocyte ratio (NLR), has been reported to have prognostic value in a variety of cancers [4], [10].

Therefore the aim of the present review was to provide a concise overview of the NLR studies in patients with cancer and comment on the current and future clinical utility of this simple objective systemic inflammation-based score.

Section snippets

Method

This systematic review of published literature was undertaken according to a pre-defined protocol. The primary outcome of interest was the relationship between the neutrophil–lymphocyte ratio and cancer outcome (overall survival/cancer-specific survival/disease recurrence or response to treatment). The secondary outcomes of interest were the associations between the NLR and other clinical, pathological or inflammatory characteristics.

A literature search, using appropriate free text and medical

Studies of the prognostic value of the NLR, in unselected cohorts of patients with cancer

Three studies, comprising data on 21,193 patients reported the prognostic value of the NLR in unselected cohorts of patients with cancer (Table 1, Refs. [11], [16], [17]). Two studies specifically assessed the prognostic value of the NLR, while one compared the NLR with other well recognised markers of the systemic inflammatory response in cancer, notably C-reactive protein, albumin, and platelets and their combinations in the prognostic scores mGPS and platelet-lymphocyte ratio (PLR). Two

Studies of the prognostic value of the NLR in patients with operable cancer

Thirty-four studies, comprising data on 12,426 patients have investigated the prognostic value of the neutrophil–lymphocyte ratio in patients with a variety of solid organ malignancies including colorectal, gastric, oesophageal, pancreatic, liver, urological and gynaecological cancers (Table 2, Refs. [8], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49]).

Studies of the prognostic value of the NLR in patients with operable cancer who received neoadjuvant therapy

Six studies, comprising data on 1044 patients have reported the prognostic value of the NLR in patients who received neo-adjuvant therapy and subsequently underwent cancer resection (Table 3, Refs. [50], [51], [52], [53], [54], [55]).

Three of these studies, comprising data on 470 patients, were in hepatocellular carcinoma (HCC) [50], [51], [52]. One study was from the USA, one was from Italy, and one from Japan. Among these studies it was consistently reported that elevated NLR was associated

Studies of the prognostic value of the NLR in patients receiving chemo/radiotherapy

Twelve studies, comprising data on 2156 patients, reported the prognostic value of the NLR in patients with cancer receiving chemotherapy, radiotherapy or a combination of both (Table 4, Refs. [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67]). Three studies, comprising data on 579 patients, reported the prognostic value of the NLR in patients with colorectal cancer receiving chemotherapy [56], [57], [58]. The NLR was reported to have prognostic value independent of tumour

Studies of the prognostic value of the NLR in patients with inoperable cancer

Six studies, comprising data on 1248 patients reported the prognostic value of the NLR in patients with inoperable cancer (Table 5, Refs. [68], [69], [70], [71], [72]). Two studies were in advanced colorectal cancer and comprised data on 399 patients, one study was from Japan and another from Australia. Both studies reported an association between elevated NLR and poorer survival in advanced colorectal cancer. In addition, both studies reported an association with hypoalbuminaemia and that

Relationships between clinicopathological factors and NLR

Several of the studies identified in this review examined factors associated with an elevated NLR. In unselected patients with breast cancer elevated NLR was associated with advancing age, larger tumours, and stage of disease. Further, increasing tumour stage was also associated with elevated NLR in patients with operable cancers, namely colorectal, gastro-oesophageal hepatocellular, lung. In addition, factors that represent more aggressive tumour behaviour, such as increased tumour size,

Discussion

The hypothesis that haematological markers of the systemic inflammatory response, in particular the neutrophil–lymphocyte ratio, reliably predict survival in patients with malignancy is one that has garnered a lot of interest in the last decade. Many groups have investigated the prognostic value of the NLR in a variety of tumours and at differing stages of disease.

It is clear that there are important associations between the NLR and other markers of the systemic inflammatory response in

Conflict of interest

There is no conflict of interest to declare.

Reviewers

Akiyoshi Kinoshita, MD, Division of Gastroenterology and Hepatology, The Jikei University Daisan Hospital, 4-11-1 Izumihon-cho, Komae-shi, Tokyo 201-8601, Japan.

Mitsuru Ishizuka, MD, Department of Gastroenterological Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan.

Basem Azab, MD, Staten Island University Hospital, Department of Medicine, 475 Seaview Avenue, New York, Staten Island 10305, United States.

Graeme J.K. Guthrie is a Clinical Research Fellow at the University of Glasgow Academic Department of Surgery and is currently undertaking research into the cell-signalling pathways involved in inflammatory responses in patients with colorectal cancer as part of an MD degree. His qualifications include: BSc (Honours) Pharmacology (University of Aberdeen), MBChB (University of Glasgow), MRCS (Royal College of Surgeons of Glasgow).

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    Graeme J.K. Guthrie is a Clinical Research Fellow at the University of Glasgow Academic Department of Surgery and is currently undertaking research into the cell-signalling pathways involved in inflammatory responses in patients with colorectal cancer as part of an MD degree. His qualifications include: BSc (Honours) Pharmacology (University of Aberdeen), MBChB (University of Glasgow), MRCS (Royal College of Surgeons of Glasgow).

    Kellie A. Charles (PhD) is senior lecturer in Pharmacology, University of Sydney. Her research interests are to understand the role of inflmmation in tumour progression and chemotherapeutic drug response. Dr. Charles conducts translational and clinical studies aimed to identify new molecular targets in cancer and in collaboration with biological chemists at the University of Sydney design and evaluate new cancer therapeutic agents.

    Campbell S.D. Roxburgh (PhD) works along with Guthrie. Clinical Lecturer at the University of Glasgow Academic Department of Surgery.

    Paul G. Horgan (PhD) is Consultant General & Colorectal Surgeon and Head of the Academic Department of Surgery, University of Glasgow.

    Donald C. McMillan (PhD) is Professor of Surgical Science at the University of Glasgow Academic Department of Surgery. The Unit concentrates on translational clinical research in surgery, particularly in colorectal cancer. Work carried out in the Academic Department of Surgery at Glasgow Royal Infirmary has highlighted the importance of the systemic inflammatory response in patients with colorectal cancer.

    Stephen J. Clarke is a medical oncologist and pharmacologist with major clinical research interests in colorectal cancer. Professor Clarke is the Director of the Translational Cancer Research Unit, a Senior Staff Specialist in Medical Oncology and Professor of Medicine at Royal North Shore Hospital, St. Leonards, Sydney, Australia.

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