*2.2.1. Local tumour spread: T*

Significant association between NLR and the invasion depth of gastric cancer is recognised since the early studies [65] and confirmed by more recent research [20]. The applied cut-off levels again vary widely. Thus, the association with increased depth of invasion has been demonstrated in patients whose high preoperative NLR level was defined as higher than or equal to 4.02 [16] or as exceeding the ROC-set cut-off value of 1.59 [55]. Significant difference in T1–2 vs. T3–4 distribution was reported by Deng et al. The mean NLR was 4.02 in T1–2 cases and 6.54 in T3–4 cases [47].

Many studies have highlighted the association between NLR and serosal invasion that is classified as T4a. Such invasion represents a potential limit to surgical treatment if followed by extensive peritoneal spread. NLR studies in regard to the tumour spread have led to the development of complex predictive scores to forecast serosal invasion. Hence, high NLR can be used as an independent predictive factor for T4 using cut-off 3.2 [73]. The high NLR (exceeding 3.44) group had significantly higher proportion of T4 when 1030 patients with resectable gastric cancer were assessed [22]. Serosal invasion was significantly more frequent in elderly patients having high NLR: 75.5% vs. 57.4% [23]. Finally, in a large prospective study enrolling 1131 surgically treated patients, high NLR (exceeding the median 3.5) was associated with deeper invasion: T3– T4 tumours. The mean NLR was 2.51 in T3–T4 tumours vs. 2.19 in T1–T2 tumours. Within the frames of a complex score, NLR can be used to predict inappropriateness of gastrectomy [54].

The capacity of NLR to predict such tumour spread that would limit surgical treatment has been explored in combined model searching for either peritoneal or metastatic spread due to either gastric or oesophageal adenocarcinoma. Authors concluded that NLR reaching or exceeding


The cut-off levels vary widely among the studies. Most frequently, either the median value is selected as the cut-off [16, 70], or the relevant level is found by receiver operating characteristic curve (ROC) analysis [30, 39]. Youden Index has been successfully employed to detect the optimal cut-off during ROC analysis [30]. This index is defined as the cut-off value showing the highest sum of specifity and sensitivity at the considered value; minus 1 [71]. Less frequently, the 75th percentile is used as the cut-off [44, 53]. Some research groups have applied more complex approach, e.g. combining the patients groups with similar survival [17, 20]. The reported

Interestingly, different cut-off values can reveal different information. Thus, Jung et al. has reported that cut-off 2.0 based on the median value was valuable in order to show that higher NLR is an independent risk factor for worse overall survival. However, when studying cancer-free survival, NLR was an independent risk factor by cut-off 3.0 corresponding to the 75th percentile [53]. The necessity for different cut-offs in regard to the question of interest is indirectly demonstrated by mean NLR in different patient groups: 4.02 in T1–2; 6.54 in T3–4; 4.81 in N0; 6.41 in N+; 5.00 in M0; 7.82 in M1; 4.74 in stage I–II cancers and 7.07 in stage III–IV cancers [47]. Jung et al. also observed statistically significant differences in median NLR by

Significant association between NLR and the invasion depth of gastric cancer is recognised since the early studies [65] and confirmed by more recent research [20]. The applied cut-off levels again vary widely. Thus, the association with increased depth of invasion has been demonstrated in patients whose high preoperative NLR level was defined as higher than or equal to 4.02 [16] or as exceeding the ROC-set cut-off value of 1.59 [55]. Significant difference in T1–2 vs. T3–4 distribution was reported by Deng et al. The mean NLR was 4.02 in T1–2

Many studies have highlighted the association between NLR and serosal invasion that is classified as T4a. Such invasion represents a potential limit to surgical treatment if followed by extensive peritoneal spread. NLR studies in regard to the tumour spread have led to the development of complex predictive scores to forecast serosal invasion. Hence, high NLR can be used as an independent predictive factor for T4 using cut-off 3.2 [73]. The high NLR (exceeding 3.44) group had significantly higher proportion of T4 when 1030 patients with resectable gastric cancer were assessed [22]. Serosal invasion was significantly more frequent in elderly patients having high NLR: 75.5% vs. 57.4% [23]. Finally, in a large prospective study enrolling 1131 surgically treated patients, high NLR (exceeding the median 3.5) was associated with deeper invasion: T3– T4 tumours. The mean NLR was 2.51 in T3–T4 tumours vs. 2.19 in T1–T2 tumours. Within the frames of a complex score, NLR can be used to predict inappropriateness of gastrectomy [54]. The capacity of NLR to predict such tumour spread that would limit surgical treatment has been explored in combined model searching for either peritoneal or metastatic spread due to either gastric or oesophageal adenocarcinoma. Authors concluded that NLR reaching or exceeding

cut-off levels for NLR in gastric cancer patients are summarized in **Table 2**.

gastric cancer stage: 1.88 in stage III and 2.17 in stage IV [53].

**2.2. Association with tumour features**

*2.2.1. Local tumour spread: T*

154 Gastric Cancer

cases and 6.54 in T3–4 cases [47].



**Study group** **Characteristics**

Consecutive patients

404

3.0

undergoing curative

gastrectomy

Curative surgery for

288

2.7

ROC analysis for

OS

Multivariate

Higher NLR is an

[49]

independent risk

factor for worse OS

Density of CD4 Ly

is decreased in high

NLR group while CD3

and CD8 + Ly density

shows no differences

Immune cell

density within

cancer

survival

gastric cancer

Operable GC Curative resection, D2

873

2.3

ROC analysis

OS

Kaplan-Meier

Although NLR is

[30]

associated with OS,

a complex score

including NLR and

albumin is more

potent predictor of OS

based on higher AUC

in ROC analysis

analysis

Multivariate

lymphadenectomy,

adjuvant chemotherapy

in high-risk stage II–III

Elderly patients

160

1.83

ROC analysis

OS

Multivariate

Higher NLR is an

[23]

independent risk

factor for worse OS

(at least 75 years

old) undergoing

gastrectomy

Surgically treated GC

601

1.7

ROC analysis

OS

Multivariate

Higher NLR is an

[48]

independent risk

factor for worse OS

492

1.59

ROC analysis

N

Multivariate

High NLR is an

[55]

independent factor,

associated with N+

**Size**

**Value**

**Approach**

ROC analysis

OS

Multivariate

Higher NLR is an

[9]

independent risk

factor for worse

OS, CSS and postoperative infectious

complications

CSS

Post-operative

complications

**Cut-off**

**Study target**

**Level of** 

**Main conclusions**

**References**

156 Gastric Cancer

**justification**



**Study group** **Characteristics**

Surgically treated GC,

1131

3.5

including non-radical

cases

Surgically treated GC

220

2.15

75th percentile

OS

Multivariate

Higher NLR is a

[44]

significant risk factor

for OS by univariate

but not multivariate

analysis

patients

Surgically treated GC,

262

3.2

ROC analysis

T4

Multivariate

High NLR is an

[73]

independent factor,

associated with T4

T2–4

Gastrectomy with

293

2.0

Median

OS

Multivariate

Higher NLR is an

[53]

independent risk

factor for worse OS

curative intent for stage

III–IV GC

Gastrectomy with

293

3.0

75th percentile

CFS

Multivariate

Higher NLR is an

[53]

independent risk

factor for worse CFS

curative intent for stage

III–IV GC

Curative gastrectomy

**Advanced, unresectable and/or metastatic GC**

Metastatic gastric

256

3

Refs. [53, 66]

OS

Multivariate

NLR is an independent

[26]

risk factor

adenocarcinoma treated

by chemotherapy

157

5.0

Refs. [74, 75]

CSS

Multivariate

Higher NLR is an

[65]

independent risk

factor for worse CSS

**Size**

**Value**

**Approach**

Median

Resection line

Mann Whitney

High NLR is

[54]

associated with T3-4,

G3-4, larger tumours,

higher N and TNM

test

Fisher test

Univariate

analysis

stage

Within frames of

complex score NLR

can be used to predict

inappropriateness of

gastrectomy

status

Tumour

characteristics

**Cut-off**

**Study target**

**Level of** 

**Main conclusions**

**References**

158 Gastric Cancer

**justification**


Abbreviations: OS, overall survival; NLR, neutrophil to lymphocyte ratio; GC, gastric cancer; Ref., reference; N+, presence of metastases in regional lymph nodes; ROC, receiver operating characteristic curve; N, regional lymph node status in respect to metastases by tumour-nodes-metastasis (TNM) classification; R0, resection line free of tumour; PLR, platelet to lymphocyte ratio; AUC, area under the curve; T, local spread of primary gastric cancer by TNM classification; LN, lymph node; MTS, metastasis; CSS, cancer-specific survival; CD, cluster of differentiation; Ly, lymphocyte; CFS, cancer-free survival; GPS, Glasgow prognostic score; TNM, tumour-nodes-metastasis classification; G, grade; PFS, progression-free survival.

**Table 2.** Cut-offs of NLR in gastric cancer studies. the cut-off value of 3.28 is an independent predictor of undesirable tumour spread. The median NLR in operable patients vs. those having peritoneal or metastatic disease was 2.2 vs. 3.3 [76].

Negative findings have been published. Some of them could be easily explained by small group size, e.g. only 61 gastric cancer patients were enrolled in the study of Pietrzyk et al. [18]. However, no differences in T distribution by NLR were found by Kim et al. who analysed a large group of 601 patients [48]. No association between invasion depth and NLR was found in a multicentre study [61].

Large tumour size has shown association with high NLR [20, 22, 38, 53–55, 65, 77]. As T in gastric cancer is not defined by size, tumour size could become a confounding factor.
