**6. Complex SIR-based scores in pancreatic ductal adenocarcinoma: presence and future**

Considering the complexity of carcinogenesis and inflammation, any single parameter has limitations and shortcomings, reflected in the controversial reports. To improve the efficacy of SIR parameters, combinations of those have been tested.

### **6.1. Combination of baseline and dynamic estimates of NLR**

In advanced PDAC, several teams have explored the combination of baseline NLR and dynamics upon the influence of chemotherapy [32]. The baseline value is scored as high or low in regard to threshold level. The cut-offs in SIR studies frequently are identified by ROC analysis or by median value. The dynamics is scored as either increase or decrease in response to the treatment; ratio between NLR in a predefined time point during treatment versus pre-treatment NLR (ratio < 1 is analogous to decrease) or high versus low value (against the threshold) in a predefined time point during treatment. The score is based on the count of adverse prognostic factors: high baseline NLR or increase of NLR upon treatment.

#### **6.2. NLR and other SIR parameters**

**5. Fibrinogen and D-dimers in pancreatic ductal adenocarcinoma**

time; p < 0.01 [73].

18 Advances in Pancreatic Cancer

Cao et al. [77].

metastasis [19, 74].

grade [73].

Extensive alterations of blood clotting have been demonstrated in pancreatic cancer patients. Sun et al. characterised different coagulation parameters in 139 patients diagnosed with pancreatic cancer and compared the data to forty age- and gender-matched controls. Cancer patients had significantly higher level of fibrinogen (p < 0.01), D-dimers (p < 0.01), antithrombin III (p = 0.015), factor VIII (p < 0.01), as well as increased international normalised ratio (p = 0.022), longer prothrombin time (p < 0.01) and prolonged activated partial thromboplastin

Plasma fibrinogen levels are significantly higher in pancreatic cancer than in case of benign pancreatic tumours [74]. Hyperfibrinogenemia has been observed in 24.8% [19]–41.1% of pancreatic cancer patients [74]. In pancreatic cancer patients, levels of fibrinogen and D-dimers are higher before surgery, but significantly lower at the recurrence-free period after surgery; p < 0.01 [75]. Fibrinogen level in pancreatic cancer also correlates with NLR and PLR and shows negative correlation with lymphocyte to monocyte ratio [76]. Thus, in pancreatic tumours, hyperfibrinogenemia is associated with malignant course, depends on cancer presence in the body and correlates with SIR parameters. Therefore, elevated fibrinogen level can be considered a component of cancer-induced SIR. It is associated with patient's prognosis.

In 96 patients who underwent chemoradiotherapy for histologically confirmed, locally advanced PDAC, elevated fibrinogen level (≥400 mg/dL) was an independent predictor of worse overall and progression free survival [69]. Similarly, in 321 patients with locally advanced or metastatic pancreatic adenocarcinoma, high plasma fibrinogen was associated with shorter survival. It was confirmed an independent prognostic factor [76]. Wang et al. [19] also noted the association between higher levels of fibrinogen and worse prognosis. However, controversies remain. For instance, elevated preoperative concentrations of D-dimers but not fibrinogen were associated with shorter overall and progression-free survival in the study of

In PDAC, plasma fibrinogen levels increase along with higher stage. In 125 PDAC patients, higher mean fibrinogen concentration was found in stage III/ IV patients compared to those diagnosed at stage I/II. Higher levels of fibrinogen correlated with the presence of distant

D-dimers represent another blood clotting parameter that is widely studied in pancreatic cancer, including the prognostic role. Thus, elevated preoperative concentrations of D-dimers were associated with shorter overall and progression-free survival [77]. D-dimers also reflect tumour burden. Higher D-dimer levels in plasma were associated with higher stage and

Higher concentration of D-dimers predicts shorter survival and non-resectability [75]. The association between non-resectability and elevated D-dimer levels in peripheral blood was also confirmed by Durczynski et al. [78] who assessed 64 patients. The concentration of D-dimers was higher in those who had metastatic cancer in comparison with patients suffering from locally advanced disease [78]. Thus, if the pancreatic tumour seems resectable Combined SIR scores have been generated, including NLR and other SIR parameters. The results might be assessed by the count of adverse prognostic factors, for example high NLR or another parameter that exceeds the cut-off level. Summary score including NLR and PLR is the most obvious option that has been already successfully tested in other cancers, for example, gastric carcinoma [14]. This approach has been fruitful also in PDAC. In patients with locally advanced pancreatic cancer treated by chemoradiotherapy, it was noted that the combination of both elevated NLR and PLR is associated with especially low 1-year survival rate and 1-year progression-free survival rate [30]. Other combinations have been evaluated as well, for example, NLR and blood counts of regulatory T lymphocytes in resectable PDAC [79]. Combined index based on hypoalbuminemia and NLR has been advocated to evaluate the prognosis of gastric cancer [80]. Analogously, in patients receiving stereotactic radiotherapy for advanced PDAC, high NLR (>5) and low albumin levels were associated with shorter median overall survival [35].

#### **6.3. NLR and cancer burden**

Currently, there are only few data suggesting dependence of NLR on the tumour burden. The correlations with pT or size have been reported with some authors while corroborated by others. Survival studies frequently indicate the independent prognostic value of SIR. Hypothetically, SIR is a characteristic of patient's fight, and not a tumour trait. If so, higher informative value could be obtained through complex scores comprising both NLR and an estimate of tumour burden by cancer markers (such as CA 19-9 or CEA), positron emission tomography findings or clinical characteristics of the tumour, for example, the presence of distant metastases or unresectable tumour. All these approaches have been successfully tested in PDAC.

PDAC might yield fruitful research data. Hypothetically, simultaneous assessment of NLR and platelet count, or NLR along with hyperfibrinogenemia might have prognostic value in PDAC, especially, considering the marked tendency to up-regulated blood clotting in pancreatic cancer patients. NLR can also be evaluated along with GPS or mGPS, or patient's somatic,

Systemic Inflammatory Response in Pancreatic Ductal Adenocarcinoma

http://dx.doi.org/10.5772/intechopen.78954

21

In conclusion, pancreatic ductal adenocarcinoma is associated with systemic inflammatory reaction. The complex pathogenesis of SIR includes ejection of platelets, neutrophils and myeloid-derived suppressor cells from bone marrow, development of neutrophil extracellular traps and pre-metastatic niches as well as upregulated levels of acute phase proteins and blood clotting factors. Despite the biological complexity, SIR can be easily evaluated by patient friendly and cheap blood tests. NLR and PLR are the most frequently used cellular SIR parameters reflecting the balance between pro-tumourous (neutrophils, platelets) and contra-tumourous (lymphocytes) activities. Glasgow prognostic score, levels of fibrinogen and D-dimers characterise proteins that are involved in SIR and thus—in blood clotting. Significant associations with survival have been demonstrated, mostly regarding NLR in surgically treated and advanced cases. PLR is beneficial to estimate prognosis in advanced cases. Both NLR and PLR can improve the preoperative diagnostics of malignancy in pancreatic cystic tumours, while PLR can be helpful to distinguish between pseudo-tumorous chronic pancreatitis and PDAC. Complex SIR-based scores are developing in order to increase the

metabolic and/or psychological status.

**7. Conclusions**

diagnostic accuracy.

**Conflict of interest**

**Author details**

Janis Gardovskis3

Arturs Silovs1

Authors have no conflicts of interest to declare.

\*, Ilze Strumfa2

\*Address all correspondence to: arturs.silovs@rsu.lv

1 Faculty of Medicine, Riga Stradins University, Riga, Latvia

2 Department of Pathology, Riga Stradins University, Riga, Latvia

3 Department of Surgery, Riga Stradins University, Riga, Latvia

, Reinis Riekstins1

, Zane Simtniece2

, Andrejs Vanags3

and

In metastatic pancreatic cancer, a combined score of pre-treatment NLR and CA 19-9 was found to be superior to either parameter alone [81]. In resectable pancreatic cancer, the 2-year overall survival rate was significantly lower in those presenting with high preoperative NLR in combination with high CA 19-9 versus the patients having both values in the low range: 37.5 versus 89.9%, respectively [82]. A complex score including NLR along with metabolic activity detected by positron emission tomography (PET) has been found informative [83]. To predict the overall survival of PDAC patients receiving palliative chemotherapy, NLR ≥ 5 was incorporated in a complex score, designated the prognostic index. The other parameters within the framework of this score were performance status, presence of distant metastases or unresectable tumour, as well as high CEA or CA 19-9 [40].

#### **6.4. Fibrinogen-based complex scores**

Similarly to NLR, fibrinogen level has been successfully incorporated in complex scores along with other SIR parameters, for example, GPS, or tumour burden, reflected by stage and/or tumour markers, for example, CA19-9. In cancers of other organs, fibrinogen has also been assessed along with D-dimer levels or NLR [14].

In 96 patients who underwent chemoradiotherapy for histologically confirmed, locally advanced PDAC, Glasgow prognostic score (of 2) and fibrinogen (≥400 mg/dL) were independent predictors of worse overall survival and progression free survival. Complex score based on fibrinogen and GPS had prognostic value [69].

In a large cohort of patients (321 cases) with locally advanced or metastatic pancreatic adenocarcinoma, high plasma fibrinogen was shown to be an independent prognostic factor. It was incorporated in a predictive model along with tumour stage and CA 19-9 level, improving the predictive capability [76].

Prognostic model for overall survival was elaborated on the basis of independent prognostic factors, identified in 125 PDAC patients by the Cox proportional hazard model. These factors comprised plasma fibrinogen, cancer stage and the presence of distant metastasis [19].

### **6.5. SIR-based complex scores: Future developments in PDAC**

Carcinomas of different organs differ markedly by their molecular pathogenesis, prognostic factors and involvement of the inflammation in various stages of carcinogenesis. In addition, even cancers of the same organ are heterogeneous, adding complexity to any cancer research. Nevertheless, the keynotes of SIR-based prognostic scores elaborated in cancers other than PDAC might yield fruitful research data. Hypothetically, simultaneous assessment of NLR and platelet count, or NLR along with hyperfibrinogenemia might have prognostic value in PDAC, especially, considering the marked tendency to up-regulated blood clotting in pancreatic cancer patients. NLR can also be evaluated along with GPS or mGPS, or patient's somatic, metabolic and/or psychological status.
