**1. Introduction**

Gastric cancer remains an important issue in world oncology. In 2013, it ranked fifth by the global incidence and second by mortality [1]. Although the death rates have decreased significantly in the USA and Europe over the previous 70 years, gastric cancer is characterised by poor prognosis and high mortality [2] except for early diagnosed cases. Thus, prognostic and predictive estimates are necessary to guide the intensity of treatment and to predict the efficacy of it. Different directions of prognostic evaluation have been studied, including classic means as tumour-node-metastasis (TNM) stage or patient's Eastern Cooperative Oncology Group (ECOG) performance status [3], or novel approaches as the molecular tests [4].

Many tumours, including gastric cancer, evoke systemic inflammatory reaction (SIR). The systemic effects of cancer include alterations in bone marrow function, especially myelopoiesis. The production and release of leukocytes increases. In addition, immature myeloid cells, including the precursors of granulocytes and monocytes, are retained in early stages of differentiation. Immature myeloid cells can act as immune suppressors and generate pre-metastatic niches, among other pathogenetic processes. Thus, it has even been stated that cancer is an inflammatory disease [5]. SIR shows complex associations with the local immune and inflammatory infiltrate in the tumour [6].

Cancer-related SIR involves cells of innate and adaptive immunity as well as soluble factors. Macrophages are recruited in tumour by hypoxia and tumour-released molecular agents including growth factors and cytokines [7]. Macrophage phenotype switch from tumoursuppressing classical M1 to tumour-promoting M2 subtype promotes angiogenesis and immunosuppression. Platelets undergo activation that contributes to cancer progression and patient mortality [8]. Neutrophil activation can stimulate angiogenesis and metastatic spread. Neutrophil extracellular traps formed from externalised DNA network are bidirectionally associated with platelet activation and can contribute to cancer progression via several mechanisms therefore neutrophil extracellular traps represent also an attractive treatment target [8]. Neutrophils are locally recruited in the cancer as well via chemokine signalling; they contribute to angiogenesis and increased blood vessel permeability. These molecular events highlight also the association between infection or surgery-induced inflammation [9, 10] and cancer relapse or metastatic spread. While innate immunity is generally thought to act as tumour enhancers, high numbers of infiltrating neutrophils [11] and macrophages [12] are shown to be protective in gastric cancer.

In contrast, lymphocytes representing the adaptive immunity are considered to have tumour suppressing effects [7] although contrary effects have been ascribed to certain subpopulations [13, 14].

There is increasing body of evidence that patients' survival can vary despite equal TNM parameters. In turn, cancer can cause systemic inflammatory response that might be associated with prognosis and/or response to treatment. SIR can be evaluated by number or ratio of serum neutrophils, lymphocytes, monocytes and platelets as well as by concentrations of acute phase proteins. These blood tests represent patient-friendly, widely available, globally standardised and cheap information that should be wisely incorporated in patients' treatment [15]. Regarding the diagnostics of gastric cancer, several SIR parameters have been found to differ between gastric cancer patients and healthy controls. Such indicators include neutrophil to lymphocyte ratio [16–18], platelet to lymphocyte ratio, platelet count [18], mean platelet volume [18, 19] and red blood cell distribution width [18]. While these changes clearly indicate activation of systemic inflammatory reaction in gastric cancer, additional research is necessary to identify the diagnostic value of SIR parameters in the differential diagnosis between gastric cancer and other gastric pathologies, including precancerous, inflammatory and ulcerative changes.

**1. Introduction**

144 Gastric Cancer

matory infiltrate in the tumour [6].

protective in gastric cancer.

[13, 14].

Gastric cancer remains an important issue in world oncology. In 2013, it ranked fifth by the global incidence and second by mortality [1]. Although the death rates have decreased significantly in the USA and Europe over the previous 70 years, gastric cancer is characterised by poor prognosis and high mortality [2] except for early diagnosed cases. Thus, prognostic and predictive estimates are necessary to guide the intensity of treatment and to predict the efficacy of it. Different directions of prognostic evaluation have been studied, including classic means as tumour-node-metastasis (TNM) stage or patient's Eastern Cooperative Oncology

Group (ECOG) performance status [3], or novel approaches as the molecular tests [4].

Many tumours, including gastric cancer, evoke systemic inflammatory reaction (SIR). The systemic effects of cancer include alterations in bone marrow function, especially myelopoiesis. The production and release of leukocytes increases. In addition, immature myeloid cells, including the precursors of granulocytes and monocytes, are retained in early stages of differentiation. Immature myeloid cells can act as immune suppressors and generate pre-metastatic niches, among other pathogenetic processes. Thus, it has even been stated that cancer is an inflammatory disease [5]. SIR shows complex associations with the local immune and inflam-

Cancer-related SIR involves cells of innate and adaptive immunity as well as soluble factors. Macrophages are recruited in tumour by hypoxia and tumour-released molecular agents including growth factors and cytokines [7]. Macrophage phenotype switch from tumoursuppressing classical M1 to tumour-promoting M2 subtype promotes angiogenesis and immunosuppression. Platelets undergo activation that contributes to cancer progression and patient mortality [8]. Neutrophil activation can stimulate angiogenesis and metastatic spread. Neutrophil extracellular traps formed from externalised DNA network are bidirectionally associated with platelet activation and can contribute to cancer progression via several mechanisms therefore neutrophil extracellular traps represent also an attractive treatment target [8]. Neutrophils are locally recruited in the cancer as well via chemokine signalling; they contribute to angiogenesis and increased blood vessel permeability. These molecular events highlight also the association between infection or surgery-induced inflammation [9, 10] and cancer relapse or metastatic spread. While innate immunity is generally thought to act as tumour enhancers, high numbers of infiltrating neutrophils [11] and macrophages [12] are shown to be

In contrast, lymphocytes representing the adaptive immunity are considered to have tumour suppressing effects [7] although contrary effects have been ascribed to certain subpopulations

There is increasing body of evidence that patients' survival can vary despite equal TNM parameters. In turn, cancer can cause systemic inflammatory response that might be associated with prognosis and/or response to treatment. SIR can be evaluated by number or ratio The correlation between neutrophil to lymphocyte ratio (NLR) and poor survival of gastric cancer patients is the best-known finding regarding SIR in gastric cancer [16, 17, 20]. High NLR is associated not only with shorter overall survival but also with worse progression-free survival [21]. In addition to the general association with survival, the prognostic value of NLR has been tested in specific clinical groups. Thus, NLR predicts post-operative survival of surgically treated patients with resectable cancer [22] and retains independent prognostic role in elderly patients—an expanding group in Western population showing multiple ageing-related changes that could affect the immune and inflammatory processes [23]. For patients undergoing chemotherapy because of unresectable and recurrent advanced gastric cancer, NLR also shows independent prognostic significance [24]. NLR is an independent prognostic factor in metastatic gastric cancer [25] and in metastatic gastric cancer treated with chemotherapy [26]. The predictive value is limited in patients receiving palliative treatment for disseminated gastric cancer [21]. Some authors consider low NLR as an indicator for good prognosis and thus beneficial effect of surgical treatment in stage IV gastric cancer [27, 28].

Some research groups have found that complex assessment of SIR-related parameters has superior prognostic value. For instance, joint analysis of platelet count and NLR was found to predict post-operative survival more exactly [29]. Combined scoring of albumin and neutrophil to lymphocyte ratio was independently associated with overall survival and was especially accurate for patients with stage I–II gastric cancer [30]. Combined evaluation of pre-operative NLR and platelet to lymphocyte ratio (PLR) was independent predictor of survival after curative surgical resection of stage I–II gastric cancer [31].

SIR can highlight wider scope of clinical traits, including manifestations that are not directly related to surgery or oncologic treatment. For example, pre-operative anxiety and depression are significantly associated with NLR [32].

SIR assessment is more comprehensive than NLR analysis. Thus, pre-operative plasma fibrinogen increases with gastric cancer stage and predicts worse recurrence-free and overall survival [33]. Similarly, levels of plasma albumin or the characteristics of platelets can provide significant data. Levels of C-reactive protein, original or modified Glasgow prognostic score can be used for analysis [3, 15].

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 survival after gastrectomy [9].

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 locally advanced tumour.

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 cancer [38].

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; complex assessment hypothetically could be advised.

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.
