Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 
ORIGINAL ARTICLE
Ahead of print publication  

The hematologic inflammatory index is a new prognostic marker in patients resected for gastric cancer


 Ankara Dışkapı Yıldırım Beyazıt Training and Research Hospital, Medical Oncology, Ankara, Turkey

Date of Submission03-Aug-2019
Date of Acceptance19-Dec-2019
Date of Web Publication22-Jul-2020

Correspondence Address:
Hayriye Sahinli,
Ankara Diskapi Yildirim Beyazit Training and Research Hospital, Ankara
Turkey
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_560_19

 > Abstract 


Background: The role of the systemic inflammatory response in cancer has been shown in many studies. The present study aims to investigate the prognostic significance of a new hematologic index obtained by the combination of platelet, neutrophil, and lymphocyte counts in patients undergoing curative gastrectomy for gastric cancer.
Methods: We retrospectively analyzed 95 consecutive patients who underwent curative gastrectomy for gastric cancer between January 2013 and December 2018. Receiver operating characteristics curve analysis was used to determine the optimal cutoff values for hematologic inflammatory index (HII). The optimal cutoff value for HII was 2.69. Baseline parameters categorized into two groups were compared with the Chi-square test. Variables were evaluated by the univariate analysis were further assessed by the multivariate analysis using Cox's proportional-hazards regression model.
Results: According to HII, 44 patients (46.3%) had values lower than 2.69 and 51 patients (53.7%) had values higher than 2.69. HII was significantly correlated with depth of tumor invasion (P = 0.009), tumor histologic type (P = 0.048), and need for adjuvant therapy (P = 0.04). Median disease-free survival (DFS) (P = 0.003, hazard ratio (HR), 0.423; 95% confidence interval [CI], 0.234–0.762) and median overall survival (OS) (P = 0.002, HR, 0.385; 95% CI, 0.207–0.716) were found to be significantly shorter in the patient group where HII was higher than 2.69 compared to the patient group whose HII was lower than 2.69. When the multivariate analysis was performed, both DFS (P = 0.025, HR, 0.484; 95% CI, 0.257–0.912) and OS (P = 0.04, HR, 0.497; 95% CI, 0.255–0.970) were found to be independent prognostic factors.
Conclusions: In this retrospective study, HII is independently associated with both DFS and OS in gastric cancer. HII is an inexpensive, powerful, and easily accessible prognostic marker.

Keywords: Gastric cancer, lymphocytopenia, neutrophilia, prognosis, thrombocytosis



How to cite this URL:
Sahinli H, Türker S. The hematologic inflammatory index is a new prognostic marker in patients resected for gastric cancer. J Can Res Ther [Epub ahead of print] [cited 2020 Aug 12]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=290469




 > Introduction Top


Gastric cancer is the fifth-most common cancer. It is also the third-most common cause of cancer-related deaths.[1] Despite the advances in the diagnosis and treatment of gastric cancer, the recurrence occurs in 1/3 of patients after curative surgery.[2],[3],[4] The prognosis in gastric cancer is mainly associated with the tumor, node, metastasis (TNM) stage.[5] However, even in the same tumor stage, the clinical outcomes of patients may be different.[6] Therefore, new studies are being conducted for new biomarkers that affect prognosis.

The role of inflammatory cells in tumor development is known. The prognosis of the patient with cancer does not depend solely on tumor-related factors. It was also found to be due to host-immune factors. In particular, a relationship between systemic inflammatory response and tumor progression has been reported.[7],[8]

The high platelet count in many cancers has been associated with a poor prognosis.[9] Increased neutrophil count and/or decreased lymphocyte count suppresses natural killer (NK) cells. As a result, the tendency of the tumor to metastasis increases.[10]

Hematological parameters such as neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio, and neutrophil-platelet score are prognostic factors in various malignancies.[11],[12],[13],[14],[15] This study aimed to show the prognostic effect of the hematological inflammatory index (HII) in patients with operated gastric cancer and to investigate its clinical significance.


 > Methods Top


This study included 95 patients with gastric cancer who underwent curative surgery for gastric cancer in Ankara Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey, between 2013 and 2018. The inclusion criteria in the study were as follows: (1) patients diagnosed with gastric cancer histopathologically; (2) patients operated for curative purposes; (3) patients who had not received anti-inflammatory therapy before surgery; and (4) patients who had undergone laboratory tests before treatment. The exclusion criteria were as follows: (1) patients with the active infection before surgery and (2) patients with autoimmune inflammatory disease. All cases were staged according to the TNM classification system of the American Joint Committee on Cancer (7th edition, 2010). All patients underwent standard subtotal or total gastrectomy with D2 lymph node dissection.

Patients' age, sex, operation history, adjuvant treatment status, histopathological characteristics (pathological TNM stage, depth of invasion, lymph node metastasis status, perineural invasion, lymphovascular invasion, and tumor differentiation), neutrophil, lymphocyte, thrombocyte counts, and hemoglobin values before treatment were retrospectively analyzed. Hematological parameters (neutrophil, lymphocyte, and platelets) were analyzed from the venous blood samples before treatment.

The overall survival (OS) was defined as the time from the date of diagnosis to the date of death or last visit. Disease-free survival (DFS) was defined as the time from diagnosis to relapse, death or the last follow-up. Hematological parameters were divided into two groups. Cutoff values: platelets ≥350 × 109/L, neutrophils ≥7.5 × 109/L, lymphocytes, 1.4 × 109/L, and hemoglobin <12 mg/dl. HII was calculated by dividing the platelet count/neutrophil count by the lymphocyte count and multiplying it by 100. The optimal cutoff values of HII were estimated by the receiver operating characteristics (ROC) curve. The area under the curve, specificity, and sensitivity were calculated. The HII cutoff value was 2.69. The baseline characteristics and significance between the two groups were evaluated by the Chi-square test. OS and DFS between groups were compared with the Kaplan–Meier method and log-rank test. Univariate and multivariate analyses (Cox proportional-hazard regression model) were performed to evaluate the prognostic factors. All P values <0.05 were considered statistically significant. Statistical analysis was performed using the SPSS software version 20.00 IBM SPSS, version 20.0 (SPSS, Chicago, IL, USA). This study was conducted according to the principles of the Declaration of Helsinki.


 > Results Top


The median age was 62 years (range: 22–84). Sixty-nine (72.6%) patients were male. The median OS was 33 months. The median DFS was 26 months. During follow-up, 52 (54.7%) patients developed recurrence, and 48 (50.5%) patients died. When the patients were divided into two groups as lower than 2.69 and higher than 2.69 according to the HII value, 44 (46.3%) patients were found to be lower than 2.69, and 51 (53.7%) patients were found to be higher than 2.69. The area under the ROC curve was 0.651 (95% confidence interval [Cl]: 0.538–0.764). The best cutoff value of platelet NLR was 2.69 according to the ROC curve, with a sensitivity of 68% and a specificity of 62% [Figure 1]. The relationship between other baseline characteristics and HII was analyzed in [Table 1] and [Table 2]. Sixty-eight (71.6%) patients received adjuvant therapy. 5-fluorouracil-based chemotherapy was given as adjuvant chemotherapy in all patients. D2 dissection was performed in all patients who underwent curative gastrectomy. Forty-five patients (47.9%) were Stage 1 and Stage 2, and 49 (52.1%) patients were Stage 3.
Figure 1: Receiver operating characteristic curves according to the values of the platelet-neutrophil-lymphocyte ratio

Click here to view
Table 1: Baseline clinicopathological characteristics of all patients and the two groups of patients with an hematologic inflammatory index <2.69 or >2.69)

Click here to view
Table 2: Baseline hematological characteristics of all patients and the two groups of patients with the hematologic inflammatory index below and above 2.69

Click here to view


HII was not associated with age, sex, TNM stage, lymphovascular invasion, perineural invasion, and lymph node status. On the contrary, patients with high HII group were more likely to have patients with T3–4 (76% vs. 50% in the low HII group) and have poorly differentiated (72% vs. 52.3% in the low HII group) tumors. In addition, the number of patients requiring adjuvant treatment was higher in the high HII group (80.4% vs. 61.4% in the low HII group) [Table 2]. Thrombocytosis (33.3% vs. 9.1% in the low HII group), lymphopenia (43.1% vs. 9.1% in the low HII group), and anemia (60.8% vs. 27.3% in the low HII group) were more common in the high HII group [Table 2].

Both the median OS and median DFS were significantly shorter in the high HII group. In the univariate analysis, a high HII above 2.69 was associated with both worse DFS [logrank P = 0.003, [Table 3]. [Figure 2] shows the DFS difference between the high and low HII groups by the Kaplan–Meier curve. DFS was significantly different when the two groups were compared. Median DFS was found to be 15 months in the group with high HII, whereas median DFS was not reached in the low HII group. The median OS was found to be 22 months in the group with high HII, but the median survival was not reached in the group with low HII [Figure 3].
Table 3: Univariate and multivariate analyses for disease-free survival

Click here to view
Figure 2: Kaplan–Meier survival curves of disease-free survival according to the platelet-neutrophil-lymphocyte ratio

Click here to view
Figure 3: Kaplan–Meier survival curves of overall survival according to hematologic inflammatory index

Click here to view


In the univariate analysis, a high HII above 2.69 was associated with both worse DFS [logrank P = 0.003, [Table 3]. [Figure 2] shows the DFS difference between the high and low HII groups by the Kaplan–Meier curve.

As a result of the univariate analysis, other factors that adversely affect DFS were determined as follows: lymphovascular invasion (logrank P = 0.015), perineural invasion (logrank P < 0.001), TNM Stage 3 disease (logrank P < 0.001), T3–4 (log-rank P < 0.001) disease, and N2–3 (log-rank P < 0.001) disease. There was no significant effect of gender, age, and histological type on DFS.

A high HII (hazard ratio [HR], 0.484; 95% CI, 0.257–0.0912, P = 0.025) was found to be an independent prognostic factor that adversely affected DFS [Table 3], as a result of cox multivariate analysis.

As a result of the univariate analysis, OS was found to be significantly shorter in the high HII group (logrank P = 0.002) [Table 4].
Table 4: Univariate and multivariate analyses of overall survival

Click here to view


In addition, univariate analysis revealed that lymphovascular invasion, perineural invasion, Stage 3 disease, N2–3 disease, and T3–4 disease had a significant adverse effect on survival [Table 4].

In a multivariate analysis model that included all factors significant for OS in univariate analysis, only high HII retained significance as factors predicting OS (HR 0.497; 95% CI, 0.255–0.970, P = 0.04) [Table 4]. As a result of multivariate analysis, it was concluded that high HII is an independent prognostic factor.


 > Discussion Top


In this study, we aimed to investigate the prognostic significance of HII in patients with operated gastric cancer. We found an association between high HII and adjuvant therapy, depth of tumor invasion, and histologic subtype. We demonstrated that high HII is an independent factor predicting poor survival in patients with operated gastric cancer.

In various studies, cancer-related inflammation has been shown to play an important role in carcinogenesis and tumor progression in many cancer types.[16],[17] The possible mechanism of inflammation may be related to malnutrition, immune dysfunction, platelet activation, angiogenesis, and activation of cytokines.[18],[19]

Inflammatory cell infiltration in the tumor microenvironment and the interaction of these cells with chemokines, interleukins, and tumor necrosis factor (TNF) increase the tumor immune response leading to tumor growth.[20],[21]

Patients with cancer have abnormal platelet counts and activation. Increased platelet activation has been shown to be an important predictor of disease activation in cancer patients.[22],[23] Platelets secrete a variety of growth factors and cytokines, such as vascular endothelial growth factor and platelet-derived growth factor, that directly or indirectly lead to tumor growth, progression, and tumor spread. In addition, studies have shown that they prevent NK cells from killing tumor cells.[24],[25],[26],[27] Furthermore, thrombocytosis has been reported to be associated with metastasis and poor prognosis.[25],[28],[29]

Peripheral blood neutrophil count increased in cancer patients. The increased neutrophil count stimulates tumor angiogenesis and causes cancer progression. It may also cause tumor growth through angiogenesis as well as TNF-beta. Neutrophils have been shown to suppress T-cell proliferation and also induce apoptosis of CD8 T-cells by TNF-alpha and nitric oxide release.[30],[31],[32]

Lymphocytes are the main cells of the host immune system. They can prevent tumor progression by eliminating cancer cells.[33] Thrombocytosis, neutrophilia, and lymphopenia have been associated with a poor prognosis.[34],[35],[36] We thought that the combined use of platelets, neutrophils, and lymphocytes can be very useful in determining the prognosis of patients with operated gastric cancer. These three hematological values are reliable, quickly measurable, and inexpensive prognostic markers. The prognostic HII has never been used to predict the prognosis in cancer patients.

Platelet, neutrophil, and lymphocyte counts are routinely checked in all patients before the treatment. In our study, HII was found to be an important prognostic marker predicting survival. A statistically significant difference was found between the two groups. Survival has been shown to be worse in the high HII group.


 > Conclusions Top


As a result of this study, a new prognostic index was found which is easy to use and inexpensive to predict survival in patients with operated gastric cancer. Prospective studies are needed to confirm the results of this study and to evaluate the HII cutoff value.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.  Back to cited text no. 1
    
2.
Powell AG, Parkinson D, Patel N, Chan D, Christian A, Lewis WG. Prognostic significance of serum inflammatory markers in gastric cancer. J Gastrointest Surg 2018;22:595-605.  Back to cited text no. 2
    
3.
Zhang X, Zhang W, Feng LJ. Prognostic significance of neutrophil lymphocyte ratio in patients with gastric cancer: A meta-analysis. PLoS One 2014;9:e111906.  Back to cited text no. 3
    
4.
Mellor KL, Powell AG, Lewis WG. Systematic review and meta-analysis of the prognostic significance of neutrophil-lymphocyte ratio (NLR) after R0 gastrectomy for cancer. J Gastrointest Cancer 2018;49:237-44.  Back to cited text no. 4
    
5.
Zhang Y, Lu JJ, Du YP, Feng CX, Wang LQ, Chen MB. Prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in gastric cancer. Medicine (Baltimore) 2018;97:e0144.  Back to cited text no. 5
    
6.
Shah MA, Ajani JA. Gastric cancer – An enigmatic and heterogeneous disease. JAMA 2010;303:1753-4.  Back to cited text no. 6
    
7.
McMillan DC. Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care 2009;12:223-6.  Back to cited text no. 7
    
8.
Roxburgh CS, McMillan DC. Role of systemic inflammatory response in predicting survival in patients with primary operable cancer. Future Oncol 2010;6:149-63.  Back to cited text no. 8
    
9.
Wang CS, Sun CF. C-reactive protein and malignancy: Clinico-pathological association and therapeutic implication. Chang Gung Med J 2009;32:471-82.  Back to cited text no. 9
    
10.
Shau HY, Kim A. Suppression of lymphokine-activated killer induction by neutrophils. J Immunol 1988;141:4395-402.  Back to cited text no. 10
    
11.
Kos FT, Hocazade C, Kos M, Uncu D, Karakas E, Dogan M, et al. Assessment of prognostic value of “neutrophil to lymphocyte ratio” and “prognostic nutritional index” as a sytemic inflammatory marker in non-small cell lung cancer. Asian Pac J Cancer Prev 2015;16:3997-4002.  Back to cited text no. 11
    
12.
Watt DG, Proctor MJ, Park JH, Horgan PG, McMillan DC. The Neutrophil-Platelet Score (NPS) predicts survival in primary operable colorectal cancer and a variety of common cancers. PLoS One 2015;10:e0142159.  Back to cited text no. 12
    
13.
Hirahara T, Arigami T, Yanagita S, Matsushita D, Uchikado Y, Kita Y, et al. Combined neutrophil-lymphocyte ratio and platelet-lymphocyte ratio predicts chemotherapy response and prognosis in patients with advanced gastric cancer. BMC Cancer 2019;19:672.  Back to cited text no. 13
    
14.
Li MX, Liu XM, Zhang XF, Zhang JF, Wang WL, Zhu Y, et al. Prognostic role of neutrophil-to-lymphocyte ratio in colorectal cancer: A systematic review and meta-analysis. Int J Cancer 2014;134:2403-13.  Back to cited text no. 14
    
15.
Tan D, Fu Y, Su Q, Wang H. Prognostic role of platelet-lymphocyte ratio in colorectal cancer: A systematic review and meta-analysis. Medicine (Baltimore) 2016;95:e3837.  Back to cited text no. 15
    
16.
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436-44.  Back to cited text no. 16
    
17.
Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004;4:71-8.  Back to cited text no. 17
    
18.
Balkwill F, Mantovani A. Inflammation and cancer: Back to Virchow? Lancet 2001;357:539-45.  Back to cited text no. 18
    
19.
Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: Integrating immunity's roles in cancer suppression and promotion. Science 2011;331:1565-70.  Back to cited text no. 19
    
20.
Nozoe T, Kimura Y, Ishida M, Saeki H, Korenaga D, Sugimachi K. Correlation of pre-operative nutritional condition with post-operative complications in surgical treatment for oesophageal carcinoma. Eur J Surg Oncol 2002;28:396-400.  Back to cited text no. 20
    
21.
Pinato DJ, North BV, Sharma R. A novel, externally validated inflammation-based prognostic algorithm in hepatocellular carcinoma: The prognostic nutritional index (PNI). Br J Cancer 2012;106:1439-45.  Back to cited text no. 21
    
22.
Leader A, Pereg D, Lishner M. Are platelet volume indices of clinical use? A multidisciplinary review. Ann Med 2012;44:805-16.  Back to cited text no. 22
    
23.
Gasparyan AY, Ayvazyan L, Mikhailidis DP, Kitas GD. Mean platelet volume: A link between thrombosis and inflammation? Curr Pharm Des 2011;17:47-58.  Back to cited text no. 23
    
24.
Palumbo JS, Talmage KE, Massari JV, La Jeunesse CM, Flick MJ, Kombrinck KW, et al. Platelets and fibrin (ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 2005;105:178-85.  Back to cited text no. 24
    
25.
Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer 2011;11:123-34.  Back to cited text no. 25
    
26.
Suzuki K, Aiura K, Ueda M, Kitajima M. The influence of platelets on the promotion of invasion by tumor cells and inhibition by antiplatelet agents. Pancreas 2004;29:132-40.  Back to cited text no. 26
    
27.
Tsuji T, Sawai T, Yamashita H, Takeshita H, Nakagoe T, Shindou H, et al. Platelet-derived endothelial cell growth factor expression is an independent prognostic factor in colorectal cancer patients after curative surgery. Eur J Surg Oncol 2004;30:296-302.  Back to cited text no. 27
    
28.
Nash GF, Turner LF, Scully MF, Kakkar AK. Platelets and cancer. Lancet Oncol 2002;3:425-30.  Back to cited text no. 28
    
29.
Stone RL, Nick AM, McNeish IA, Balkwill F, Han HD, Bottsford-Miller J, et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med 2012;366:610-8.  Back to cited text no. 29
    
30.
Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau CS, et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 2015;522:345-8.  Back to cited text no. 30
    
31.
Michaeli J, Shaul ME, Mishalian I, Hovav AH, Levy L, Zolotriov L, et al. Tumor-associated neutrophils induce apoptosis of non-activated CD8 T-cells in a TNFα and NO-dependent mechanism, promoting a tumor-supportive environment. Oncoimmunology 2017;6:e1356965.  Back to cited text no. 31
    
32.
Grecian R, Whyte MK, Walmsley SR. The role of neutrophils in cancer. Br Med Bull 2018;128:5-14.  Back to cited text no. 32
    
33.
Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature 2001;411:380-4.  Back to cited text no. 33
    
34.
Cho H, Hur HW, Kim SW, Kim SH, Kim JH, Kim YT, et al. Pre-treatment neutrophil to lymphocyte ratio is elevated in epithelial ovarian cancer and predicts survival after treatment. Cancer Immunol Immunother 2009;58:15-23.  Back to cited text no. 34
    
35.
Liang L, Zhu J, Jia H, Huang L, Li D, Li Q, et al. Predictive value of pretreatment lymphocyte count in stage II colorectal cancer and in high-risk patients treated with adjuvant chemotherapy. Oncotarget 2016;7:1014-28.  Back to cited text no. 35
    
36.
Cézé N, Thibault G, Goujon G, Viguier J, Watier H, Dorval E, et al. Pre-treatment lymphopenia as a prognostic biomarker in colorectal cancer patients receiving chemotherapy. Cancer Chemother Pharmacol 2011;68:1305-13.  Back to cited text no. 36
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

 
Top
 
 
  Search
 
   
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  >Abstract>Introduction>Methods>Results>Discussion>Conclusions>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed66    
    PDF Downloaded3    

Recommend this journal