Introduction
It is known that preoperative systemic inflammatory response is related to the development, progression and invasion of tumour cells and consequently to overall survival [
1] in most tumours.
Different biological parameters have been identified as markers of a systemic inflammatory state. Some of the most relevant markers are neutrophil-to-lymphocyte ratio (NLR) [
2], lymphocyte-to-monocyte ratio (LMR) [
3], platelets-to-lymphocytes ratio (PLR) [
4], Nutritional Prognosis Index ([10 × albumin] + [0,005 × lymphocytes]) [
5], Glasgow Prognosis Score (a combination of C reactive protein and albumin values) [
6], systemic immune-inflammatory index (neutrophils × platelets/lymphocytes) [
7] and derived neutrophil-to-lymphocyte ratio (neutrophil to white blood cells – neutrophils) [
8]. The most frequently analysed biomarker to evaluate systemic inflammatory response is NLR, as it is a simple, easy-to-use and inexpensive tool.
Several studies have shown that a high preoperative neutrophil-to-lymphocyte ratio (NLR) value in peripheral blood tests represents an independent prognostic factor of overall survival in different types of tumours, including gastric cancer [
3,
9].
It has also been proven that postoperative complications (especially severe and infectious ones) are independent prognostic factors for long-term survival after curative gastrectomy [
10‐
12].
Likewise, preoperative systemic inflammatory response and postoperative complications are both going to affect overall survival, but at different moments of the disease. The preoperative systemic inflammatory state is influenced by the tumour immunity and may induce anti- or pro-tumour response. The presence of postoperative complications (especially more infectious ones) could activate different pro-tumour pathways and impair survival [
13].
Given the influence on the survival of preoperative systemic inflammation and systemic inflammation following postoperative complications, both factors should be analysed together to ensure the independent predictive value of each parameter.
The aim of this study was to determine if the prognostic value of the preoperative NLR could be influenced by the presence of postoperative complications in patients with gastric adenocarcinoma resected with curative intent.
Discussion
This study shows that the preoperative systemic inflammatory response of the host correlates with overall survival independently in patients with curative gastric cancer resection. Also, postoperative complications and their severity were associated with the worst prognosis, but the inflammatory response of postoperative complications (which differs from the inflammation produced by the oncological process) did not affect preoperative NLR.
The prognostic value of preoperative NLR has previously been reported for gastric cancer and other types of tumours [
2,
4,
21‐
27]. It is well known that peripheral blood neutrophils, lymphocytes, monocytes and platelets, as well as their combination by ratios, behave as inflammatory markers in patients with cancer and play a relevant role in tumour-related immunity. However, the relationship between blood levels and the local inflammatory tumour microenvironment has not been established to date.
Neutrophils could promote growth and metastasis of tumours through secreting cytokines, chemokines and vascular endothelial growth factor and promote adhesion between circulating tumoral cells and distant organs, increasing the chance of distant metastases [
28]. Moreover, neutrophils could also inhibit the antitumour immune function of the Natural Killer and cytotoxic T cells. Lymphocytes play a relevant role in tumour-related immunity. Several subtypes of tumour infiltrating lymphocytes such as CD8 + T cells and memory T cells are associated with better outcomes, but some subsets of T cells, regulatory T cells and Th17 cells are related to tumour progression and unfavourable prognosis. However, a high level of absolute lymphocytes count in blood is associated with an antitumour function, inhibition of tumour progression and favourable prognosis [
29].
This study showed that pT, pN, type of surgery, type of lymphadenectomy, NLR and severity of postoperative complications (C-D) were predictors of long-term survival. However, multivariate analysis showed that only pN, postoperative complications and NLR remained independent prognostic factors. These findings underline that systemic inflammatory status has an important influence on the prognosis of patients with gastric cancer, independently from tumour stage and the presence of POC, suggesting that NLR can behave as a reliable marker of the host inflammatory status against the tumour.
However, it has been described [
30,
31] that an altered preoperative inflammatory state of the patient can favour POC and these POC (especially the infectious and severe ones) are related to a higher risk of tumour recurrence. It could be argued that only morbidity itself has a real influence on long-term prognosis rather than the preoperative systemic inflammatory state [
10,
11,
30].
Our results suggest that the mechanisms through which preoperative systemic inflammatory response (NLR ≥ 2.4) influences overall survival were not mediated through the development of surgical complications. Both parameters were independent prognostic factors. This is an important concept because POC are not uncommon after gastric cancer surgery and affect almost 40% of patients in this study, the most common being anastomotic leaks (8.8%) and intraabdominal abscess (8.8%). These results are in concordance with recent studies [
32].
Our results also show the importance of the preoperative value of NLR in the prognosis and its influence on the overall survival of different anatomopathological stages (TNM classification). NLR significantly influenced stages III and IV so that patients with the same TNM stage had different overall survival according to NLR value. This phenomenon could be explained because most of the patients of our cohort had an advanced TNM stage. This is an important observation because it allows us to differentiate those patients with the same TNM stage and different long-term survival [
33,
34].
It is known that surgery and non-infectious complications (like obstruction, perforation and haemorrhage) are associated with the generation of systemic inflammatory response, resulting in the suppression of cell-mediated immunity [
35]. The development of postoperative infectious complications results in an up-regulation of innate immune response and the suppression of adaptive immunity, favouring an increased risk of recurrence [
30].
Previous hypotheses relating to surgical complications and a reduction in survival were based on the paradigm that infective complications initiate an inflammatory cascade, activate pro-inflammatory cytokines and vascular growth factors which promote tumour growth and dissemination [
36]. Although the mechanisms are not well known, the systemic inflammatory response induced by the tumour may differ from that induced by surgical trauma or infection. An elevated preoperative NLR has been associated with a greater density of CD4 + lymphocytes around the tumour, without other specific immune cells, like CD3 + or CD8 + lymphocytes, suggesting a relationship between peripheral inflammatory response and immune activation in the local tumour microenvironment [
37]. In our series, we found more infectious POC in the NLR ≥ 2.4, in line with previous studies [
31,
38], but this phenomenon did not correlate with differences in overall survival.
Taking all these reasons into account, we should differentiate preoperative tumour-related inflammation from the inflammatory mechanisms of POC, which will influence prognosis in different ways.
Another important issue in most studies is the lack of consensus on the cut-off value for NLR. One of the controversies of this type of study is the lack of standardisation to determine the cut-off value for NLR, ranging in the literature from 2 to 5 [
33,
39‐
41]. We used an NLR cut-off value of 2.4, based on the median value, with similar results to other studies [
9,
42]. However, different methods can be used to calculate NLR, such as ROC curve, median value or the use of computer X-Tile software [
29]. Because of this variability in the cut-off values, it is difficult to use preoperative NLR as a clinical standardised prognostic value. Besides, a combination of different preoperative systemic inflammatory markers (NLR, LMR, total number of monocytes and lymphocytes) may provide a better predictive value than each one alone, but this has not been confirmed to date [
43].
The limitations of this study include those related to its retrospective design, the limited number of patients, the impossibility of having a standard cut-off value for NLR and that the prognostic value of peripheral blood cells after surgery was not evaluated. More studies are needed to establish a clear cut-off value of preoperative inflammatory markers and help to find its utility in clinical practice.
In conclusion, the preoperative systemic inflammatory response in patients with gastric cancer, measured by neutrophil-to-lymphocyte ratio, behaves as an independent prognostic factor, even in those patients with postoperative complications. More prospective trials are necessary to validate these data.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.