**2.1. NLR and survival: prognostic implications**

The systemic inflammatory reaction itself can be an adverse pathogenetic event, facilitating tumour angiogenesis or adhesion of circulating tumour cells to endothelium that would lead to the growth of metastasis. In addition, NLR correlates with other factors known to have adverse prognostic role. Among such parameters, presence of vascular and lymphatic invasion as well as positive resection lines have been reported [22]. In several studies, NLR has been found to correlate with the stage of gastric cancer [16, 20–22]. NLR negatively correlates with mismatch repair protein deficiency [34]. NLR is associated with post-operative infectious complications. Both factors show an independent significant association with poorer

The evaluation of SIR in gastric cancer patients is highly attractive. By increasing awareness of SIR parameters, simple and widely available blood tests can provide information that is helpful in shaping the care of gastric cancer patients from early stages to metastatic spread or

However, unresolved issues remain. Except the prognostic value to NLR, many aspects as the correlation with tumour morphology, type by Lauren classification, invasive properties of cancer, grade, intensity of angiogenesis and microvascular density have been targeted by low number of studies. Only few meta-analyses have been conducted [21, 35–37]. Few data are available on SIR parameters after treatment although it is known that post-chemotherapy NLR correlates with the response in patients with unresectable gastric

The practical unsolved questions include the comparison between NLR and other indicators of systemic inflammatory response, e.g., platelet to lymphocyte ratio [39], the significance of post-treatment NLR as well as cut-off values for practical use. The ultimate goal would be to create and validate an algorithm for fine-tuning of the treatment strategy in gastric cancer from early to advanced stages. Inflammatory markers other than NLR should be included;

Thus, considering the high incidence and mortality of gastric cancer and the need for prognostic and predictive data, the present chapter will be devoted to the assessment of SIR in gastric cancer in order to develop practical recommendations how to adjust gastric cancer treatment by easily available and economically feasible simple blood tests for SIR parameters. Increased awareness of SIR characteristics is important to reach this aim.

Neutrophil to lymphocyte ratio is calculated as the ratio between the count of neutrophilic leukocytes and lymphocytes in peripheral blood. Thus, the parameter is easily available, especially in carefully examined cancer patients, and economically non-demanding. In fact, sufficient awareness and algorithm for interpretation are the only prerequisites to obtain an

Since the early reports [40, 41], NLR has been studied in relation to the prognosis of gastric cancer patients. Thus, Aliustaoglu et al. reported that high NLR was statistically

survival after gastrectomy [9].

locally advanced tumour.

complex assessment hypothetically could be advised.

**2. Neutrophil to lymphocyte ratio in gastric cancer**

additional piece of information from routine blood tests.

cancer [38].

146 Gastric Cancer

The prognostic importance of NLR is shown over the whole course of gastric cancer, and is applicable to wide treatment spectrum—from surgically resectable cases, including early gastric cancer, to advanced, recurrent or metastatic tumours subjected to non-surgical treatment. Most researchers have demonstrated that NLR is an independent prognostic factor, based on multivariate analysis [17]. However, in few studies, the association with survival is confirmed by univariate but not multivariate analysis [43–45]. Some of the reports are on better scores, e.g. Glasgow prognostic score had higher informativity in a large and homogeneous group of 324 patients with stage III gastric cancer undergoing resection [43].

The prognostic value of NLR has been reported in different cancers, including lung, colorectal and breast carcinoma, among others [46]. Gastric cancer also follows the same mechanisms. In unselected cohort of patients diagnosed with gastric adenocarcinoma, high NLR (compared with the cut-off value 3) was a significant (p = 0.016), independent risk factor for poor survival [17].

Surgery is the mainstay of gastric cancer treatment, if the local and/or systemic tumour spread, or the general condition of the patient does not limit the possibilities of surgical intervention. In patients who have had curative surgery for gastric cancer, high NLR is significantly associated with poor prognosis [39], including overall survival [16, 47–49], cancer-specific survival [47], cancer-free survival [16, 47] and progression-free survival [25, 38, 50].

Thus, in a recent study of 162 patients with resectable gastric cancer, high pre-operative NLR (reaching or exceeding the median of 4.02) was associated with decreased overall and cancer-free survival, confirmed by Kaplan-Meier analysis [16]. In a significantly larger group of 1986 consecutive patients subjected to curative surgical treatment for gastric cancer, NLR was confirmed as an independent prognostic factor for overall survival, associated with hazard ratio of 1.4 [39]. Similarly, in 601 surgically treated gastric cancer patients, high NLR (reaching or exceeding 1.7) was a significant prognostic parameter for overall survival, confirmed as an independent factor by multivariate analysis. The hazard ratio was 2.12 [48]. Analogous observations were reported by Hsu et al. They assessed a large cohort of 1030 gastric cancer patients subjected to complex treatment. In accordance with clinical indications, subtotal or total gastrectomy along with spleen- and pancreas-sparing D2 lymphadenectomy was performed, aiming to accomplish clear resection margins. Metastasectomy was considered depending on clinical symptoms and possibility of radical resections, and adjuvant or palliative chemotherapy was offered for stage II–IV patients. In such a large group, showing the routine clinical diversity of gastric cancer presentation, high NLR (exceeding 3.44) was an independent prognostic factor for overall survival, associated with hazard ratio of 1.57 [22].

In addition to significant statistical findings, the biological differences between groups also are remarkable. The 3- and 5-year survival rates in low versus (vs.) high NLR groups were 71.0% vs. 55.1% and 64.1% vs. 47.2%, respectively [22]. Even more, the 5-year survival was 29.9% in the high NLR group (reaching or exceeding 5.0) contrasting with statistically significantly different value of 85.6% in patients who had low NLR [51].

The overall survival was 86.1 months in patients presenting with low NLR vs. 64.0 months in high NLR (reaching or exceeding 2.3) group [30]. Evaluating 156 surgically treated gastric cancer patients, the median survival in high vs. low NLR groups was 36 vs. 60 months while the five-year survival was 35% and 60%, and the median cancer-free survival was 12 and 20 months, respectively. The survival differences retained significance in N0 patients: 5-year survival was 60% vs. 90%, p < 0.05. In this cohort, NLR was also recognised as an independent prognostic factor for overall survival [52].

In advanced gastric cancer (stage III–IV) patients subjected to gastrectomy with curative intent, high NLR was an independent predictor of overall survival at cut-off 2.0 corresponding to median while cut-off value 3.0 (the 75th percentile) was an independent predictor of cancer-free survival. The median overall survival in high vs. low NLR was 21.4 and 45.3 months while the progression-free survival in the redefined high and low NLR groups was 12.8 vs. 27.9 months [53].

NLR retains prognostic significance for surgically treated gastric cancer patients in specific subgroups. For instance, in elderly gastric cancer patients (aged 75 years or older) treated by gastrectomy, high NLR (reaching or exceeding 1.83) was associated with worse survival. Again, NLR was confirmed as an independent risk factor by multivariate analysis. The biological differences were remarkable: the median survival associated with low vs. high NLR was 1209 vs. 587 days, respectively [16]. High NLR is associated with older age in some studies [9, 20, 44, 47, 54, 55] while others report no association [22, 38].

It is very important to identify high risk of cancer progression in early diagnosed cases. Some promising reports have been published. Combined score including NLR and albumin level was shown to have independent prognostic value exceeding the informativity of NLR as justified by higher area under curve (AUC). This score, further described in detail, retained the prognostic ability in stage I–II gastric cancer [30]. A complex score comprising NLR and PLR is another prognostic option, successfully tested in a stage I–II gastric cancer. NLR-PLR score showed a clear trend to improve the prognostic value of TNM staging [31].

Mohri et al. has reported very interesting findings regarding NLR in surgically treatable gastric cancer cases. In 404 patients undergoing curative gastrectomy for gastric cancer, high NLR was an independent risk factor of post-operative infectious complications while it was not predictive of non-infectious complications. In turn, both high NLR and post-operative infectious complications were independent risk factors of worse overall and cancer-specific survival [9]. The preceding NLR increase in patients later developing post-operative infectious complications but not in case of all complications was justified by Japanese scientists [10].

subtotal or total gastrectomy along with spleen- and pancreas-sparing D2 lymphadenectomy was performed, aiming to accomplish clear resection margins. Metastasectomy was considered depending on clinical symptoms and possibility of radical resections, and adjuvant or palliative chemotherapy was offered for stage II–IV patients. In such a large group, showing the routine clinical diversity of gastric cancer presentation, high NLR (exceeding 3.44) was an independent prognostic factor for overall survival, associated with hazard

In addition to significant statistical findings, the biological differences between groups also are remarkable. The 3- and 5-year survival rates in low versus (vs.) high NLR groups were 71.0% vs. 55.1% and 64.1% vs. 47.2%, respectively [22]. Even more, the 5-year survival was 29.9% in the high NLR group (reaching or exceeding 5.0) contrasting with statistically signifi-

The overall survival was 86.1 months in patients presenting with low NLR vs. 64.0 months in high NLR (reaching or exceeding 2.3) group [30]. Evaluating 156 surgically treated gastric cancer patients, the median survival in high vs. low NLR groups was 36 vs. 60 months while the five-year survival was 35% and 60%, and the median cancer-free survival was 12 and 20 months, respectively. The survival differences retained significance in N0 patients: 5-year survival was 60% vs. 90%, p < 0.05. In this cohort, NLR was also recognised as an independent

In advanced gastric cancer (stage III–IV) patients subjected to gastrectomy with curative intent, high NLR was an independent predictor of overall survival at cut-off 2.0 corresponding to median while cut-off value 3.0 (the 75th percentile) was an independent predictor of cancer-free survival. The median overall survival in high vs. low NLR was 21.4 and 45.3 months while the progression-free survival in the redefined high and low NLR groups was

NLR retains prognostic significance for surgically treated gastric cancer patients in specific subgroups. For instance, in elderly gastric cancer patients (aged 75 years or older) treated by gastrectomy, high NLR (reaching or exceeding 1.83) was associated with worse survival. Again, NLR was confirmed as an independent risk factor by multivariate analysis. The biological differences were remarkable: the median survival associated with low vs. high NLR was 1209 vs. 587 days, respectively [16]. High NLR is associated with older age in some stud-

It is very important to identify high risk of cancer progression in early diagnosed cases. Some promising reports have been published. Combined score including NLR and albumin level was shown to have independent prognostic value exceeding the informativity of NLR as justified by higher area under curve (AUC). This score, further described in detail, retained the prognostic ability in stage I–II gastric cancer [30]. A complex score comprising NLR and PLR is another prognostic option, successfully tested in a stage I–II gastric cancer. NLR-PLR score

Mohri et al. has reported very interesting findings regarding NLR in surgically treatable gastric cancer cases. In 404 patients undergoing curative gastrectomy for gastric cancer, high NLR

cantly different value of 85.6% in patients who had low NLR [51].

ies [9, 20, 44, 47, 54, 55] while others report no association [22, 38].

showed a clear trend to improve the prognostic value of TNM staging [31].

prognostic factor for overall survival [52].

12.8 vs. 27.9 months [53].

ratio of 1.57 [22].

148 Gastric Cancer

In contrast with the previously described findings, NLR was not informative regarding survival of gastric cancer patients having only local disease while it was significantly associated with survival in advanced cases [56]. Some negative findings, including the cited one, can be explained by small study group comprising only 53 patients with local disease and 50 with advanced cancer [56]. Evaluating Glasgow prognostic score, NLR and PLR in patients with resected stage III gastric adenocarcinoma, only Glasgow prognostic score along with TNM stage was independently associated with cancer-free and overall survival [43]. If the study design includes several SIR parameters, multivariate analysis could highlight only one of those.

Advanced or metastatic cancer represents a situation with continuously significant tumour burden, associated with ongoing inflammation, angiogenesis, antigenic stimulation and thus sustained SIR. The NLR has been evaluated in these situations as well. In 174 advanced gastric cancer patients treated with oxaliplatin/5-fluorouracil (FOLFOX), NLR was associated with overall survival but not with progression-free survival. NLR was also an independent predictor of overall survival. Normalisation of NLR after one cycle of chemotherapy was significant and independent predictor of overall and progression-free survival [57]. Similar findings are reported by Jin et al. [58].

In unresectable and recurrent advanced gastric cancer patients treated by chemotherapy, high NLR (exceeding 4) was associated with significantly lower median survival [24]. Similarly, in another cohort comprising 143 cases of metastatic gastric cancer, high NLR was an independent prognostic factor. The overall and progression-free survival was 11.6 and 7.9 months in low NLR (less than 3.34) group contrasting with 8.3 and 6.2 months in patients having high NLR [25]. In 120 unresectable metastatic and advanced gastric cancer cases, treated by chemoradiotherapy, baseline NLR predicted survival. The median overall and progression-free survival in high vs. low NLR group was 10 and 3 months vs. 18 and 6 months. Treatment-induced changes in NLR also predicted survival. Both baseline NLR and changes upon initiation of treatment predicted treatment outcomes [38]. This finding is in accordance with Cho et al., who also reported significantly higher chemotherapeutic disease control rate in metastatic advanced gastric cancer patients having low NLR, defined as less or equal to 3.0 [50]. Combined scores have been generated to evaluate the prognosis of metastatic gastric cancer as well [26].

Occasionally NLR shows association with survival by univariate but not multivariate analysis. Thus, in a small group of 70 patients affected by locally advanced gastric cancer (stage III–IV) and treated by neoadjuvant chemotherapy, NLR was an independent predictor of overall survival. It was significantly associated with progression-free survival but was not an independent factor [59]. In a large group of 439 patients affected by metastatic or recurrent gastric cancer, NLR was significantly associated with overall survival in univariate but not multivariate analysis. Complex score was favoured by authors [60].

The prognostic findings regarding NLR in gastric cancer have been summarised in **Table 1**.



**Study group** **Characteristics**

Unselected gastric

706

X

Multivariate

adenocarcinoma

GC

245

X

Kaplan-Meier

analysis of

multicentre study

data

Gastric adenocarcinoma

**Surgically treated GC**

Consecutive GC patients

404

X

X

Multivariate

Multivariate

undergoing curative

gastrectomy

Curative surgery for GC

Resectable GC GC, subjected to curative

1986

X

Multivariate

surgery

Surgically treated GC

601

X

Multivariate

(R0)

GC patients undergoing

389

X

X

X

Multivariate

Multivariate

X

X

Multivariate

Multivariate

Multivariate

gastrectomy

Surgically treated GC

207

patients

GC subjected to radical

291

X

Multivariate

surgery

162

X

X

Kaplan-Meier

analysis

Kaplan-Meier

analysis

288

X

Multivariate

236

X

Multivariate

**Size**

**Survival**

**Overall**

**Cancer-specific**

**Cancer-free**

**Progression-free**

[17]

[61]

[62]

[9]

[49]

[16]

[39]

[48]

[47]

[63]

[20]

**References**

150 Gastric Cancer



**Study group** **Characteristics**

**Advanced, unresectable** 

**and/or metastatic GC**

Unresectable and

224

X

Multivariate

recurrent advanced GC,

treated by chemotherapy

Metastatic GC treated by

256

X

Multivariate

chemotherapy

Metastatic GC Unresectable, advanced

120

X

Kaplan-Meier

analysis

GC, treated by

chemotherapy

Metastatic GC treated by

109

X

Kaplan-Meier

analysis

chemotherapy

GC, stage IV with

123

X

Multivariate

synchronous distant MTS

Metastatic advanced

268

X

Multivariate

GC treated by palliative

chemotherapy

Locally advanced GC

70

X

Multivariate

treated by neoadjuvant

chemotherapy

Metastatic or recurrent

439

X

Univariate

(significant)

Multivariate (NS)

GC

143

X

Multivariate

**Size**

**Survival**

**Overall**

**Cancer-specific**

**Cancer-free**

**Progression-free**

[24]

[26]

X

[25]

Multivariate

X

[38]

Kaplan-Meier

analysis

X

[67]

Kaplan-Meier

analysis

[27]

X

[50]

Multivariate

X

[59]

Univariate

(significant)

Multivariate (NS)

[60]

**References**

152 Gastric Cancer

Abbreviations: GC, gastric cancer; R0, resection line free of cancer; NS, not significant; MTS, metastasis.

**Table 1.** The prognostic value of NLR in gastric cancer patients. 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 cut-off levels for NLR in gastric cancer patients are summarized in **Table 2**.

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

### **2.2. Association with tumour features**
