**3. PLR in pancreatic ductal adenocarcinoma**

#### **3.1. PLR and survival**

**2.2. NLR and cancer burden**

12 Advances in Pancreatic Cancer

*2.2.1. NLR and local tumour features: pT and other traits*

(p = 0.003) tumours at earlier (p = 0.02) stage [43].

*2.2.2. NLR and regional lymph node involvement: pN*

*2.2.3. NLR and presence of distant metastasis: pM*

**2.3. Diagnostic role of NLR in pancreatic tumours**

diagnostics.

general agreement that pM1 is associated with higher NLR.

by Yang et al., showing the HR = 1.69; 95% CI: 1.10–2.59; p = 0.016 [46].

If NLR in particular and SIR in general are mostly dictated by the events in cancer stroma, NLR should correlate with cancer burden, reflected by pT or cancer size. However, the data are controversial. Thus, in a study of 442 patients undergoing surgical treatment for pancreatic cancer, there was no association between NLR and tumour size or pT. No correlation was found with perineural invasion, involvement of resection margins, and invasion into blood or lymphatic vessels [21]. In contrast, high NLR (≥2) was significantly associated with pT and grade among 381 patients treated by curative resection [23]. In a recent meta-analysis of 8252 cases, lower NLR was observed in patients having smaller (p = 0.0007), better differentiated

The association between NLR and regional lymph node status also is controversial. While some research teams have observed higher NLR values in patients affected by tumour metastases in regional lymph nodes, other studies have not confirmed these findings. NLR was associated with lymph node metastasis in the study of 159 surgically treated PDAC patients [45]. Similarly, high NLR (≥2) was significantly associated with pN among 381 patients treated by curative resection [23]. In contrast, no correlation was found between NLR and cancer spread to regional lymph nodes reflected by pN or with invasion into lymphatic vessels by Sierzega et al. [21], evaluating 442 surgically treated patients. In Austrian cohort of 110 surgi-

In contrast to the previous aspects of tumour burden, namely, pT, size or pN, there is almost

In patients diagnosed with unresectable pancreatic cancer, high pre-treatment NLR significantly correlated with presence of liver metastases [8]. Distant metastases were significantly more frequently identified in patients presenting with high NLR (>5): 61.6 versus 30.1%; p < 0.0001 [38]. In advanced pancreatic cancer (including both metastatic and locally advanced cases), high NLR (≥5) correlated with the presence of metastatic disease [25]. The association between NLR and presence of distant metastases has also been confirmed by a meta-analysis

The diagnostics of PDAC is frequently a difficult issue. However, the close association between chronic pancreatitis and PDAC significantly limits the applicability of SIR for early

Baseline NLR in unresectable pancreatic cancer has been found to be significantly higher than in healthy controls: 3.81 versus 1.80; p < 0.001 [8]. Although the biological difference in the detected levels is remarkable, the comparison between advanced cancer and healthy

cally treated pancreatic cancer patients, NLR lacked correlation with stage [25].

PLR is the second best known cellular parameter characterising SIR. Similarly to NLR, most studies have concentrated on the prognostic value of PLR regarding the survival. Two meta-analyses have been published recently (2018), and both teams have reached very similar conclusions on the association between elevated PLR and worse overall survival. In a meta-analysis of 17 studies on PLR in pancreatic cancer, the negative prognostic role of high PLR was confirmed by hazard ratio for worse overall survival HR = 1.28; 95% CI: 1.17–1.40; p < 0.001 and worse progression-free survival HR = 1.27; 95% CI = 1.03–1.57; p = 0.03 [53]. In another meta-analysis of 17 studies (including 16 reports on association between PLR and overall survival in 3028 patients), high PLR also was found to be associated with worse overall survival HR = 1.22; 95% CI: 1.09–1.36; p < 0.001. Interestingly, the prognostic role was confirmed in the subgroup of Asians (HR = 1.22; 95% CI: 1.11–1.34; p < 0.001) but not Caucasians characterised by HR = 1.20; 95% CI: 0.90–1.62; p = 0.22 [54]. The same conclusion, pointing to significant role of PLR in Asia-based studies but not in those carried out in Europe, was reported earlier by Song et al., [55].

Regarding surgically treated PDAC, prognostic role has been ascribed to PLR. In 131 surgically treated PDAC patients, PLR was an independent factor predicting overall and cancer free survival [56]. In a small group of 46 patients treated with pancreaticoduodenectomy for pancreatic cancer, high PLR ≥ 200 was associated with lower overall survival and was the only independent prognostic indicator contrasting with NLR [22]. In borderline resectable PDAC, high PLR (>225) was an independent factor predicting worse survival. The median survival was 10.2 versus 24.7 months in high versus low PLR groups; p = 0.003 [57].

the pathologic response, higher mean PLR was observed in poor versus good response group: 172.9 versus 147.3; however, the difference did not reach statistical significance. NLR was superior in this study [34]. In 261 patients with inoperable pancreatic cancer (including both metastatic and locally advanced cases), high PLR (≥150) was not associated with cancer-spe-

Abbreviations: SIR, systemic inflammatory reaction; NLR, neutrophil to lymphocyte ratio; PLR, platelet to lymphocyte

**High SIR Low SIR p High SIR Low SIR p**

Systemic Inflammatory Response in Pancreatic Ductal Adenocarcinoma

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

15

**SIR parameter 1-Year overall survival rate 1-Year progression free survival rate**

**Table 3.** Prognostic estimated by PLR versus NLR in advanced pancreatic cancer [30].

NLR 73.2 60.8 <0.001 43.9 31.3 <0.001 PLR 68.1 61.3 0.029 37.9 32.5 0.027

In contrast, in a small cohort of 66 patients diagnosed with advanced pancreatic cancer, only PLR (not NLR or other SIR parameters) was associated with survival [59]. In advanced pancreatic cancer, high PLR was a significant independent prognostic marker for shorter survival. The median survival was 4.0 versus 9.1 months in patients having PLR ≥ 200 versus

Several reports indicate an important role of platelet activation in the metastatic cancer spread. PLR was significantly associated with lymph node metastasis; p < 0.001 [45]. Anti-platelet treatment, for example, by Clopidogrel, can inhibit the development of metastases [60].

Differential diagnosis between chronic pancreatitis, presenting with tumour-like mass, and pancreatic ductal adenocarcinoma, can be difficult. Although inflammation is involved in both diseases, thrombocytosis and lymphopenia are more likely to occur in patients harbouring a malignant tumour. Comparing PLR in PDAC and inflammatory masses of pancreatic head, difference was revealed: PLR was 91 (interquartile range (IQR): 77.2–106.6) in patients diagnosed with pseudo-tumorous inflammation and 161.9 (IQR: 117.5–205.6) in PDAC. By ROC analysis, PLR reached area under curve (AUC) value of 88.8%, and the sensitivity and specificity were 79.4 and 92.6%, using cut-off at 113.5 [61]. Another study assessed the diagnostic value of PLR in the distinction between inflammatory pancreatic mass and PDAC in surgically treated patients. The sensitivity and specificity of PLR was comparable to CA 19-9,

In mucinous cystic neoplasms, elevated PLR was shown to be significantly associated with presence of invasive carcinoma in 245 patients from Shanghai [47] and 318 patients from

cific survival, as confirmed by p < 0.612 [25].

**3.3. Diagnostic role of PLR in pancreatic tumours**

and combination of both improved the predictive value [62].

PLR < 200 [31].

ratio.

Singapore [48].

**3.2. PLR and metastatic spread**

However, these findings have been challenged by a lot of contrary reports. PLR did not predict survival in 217 patients treated for resectable pancreatic cancer [28]. In even larger cohort of 442 pancreatic resections for cancer, there was no association between PLR and survival although NLR was an independent predictor of poor prognosis [21]. In 159 surgically treated patients, PLR lacked prognostic value in regard to overall survival; p = 0.463 although PLR was associated with lymph node metastasis that in turn was independent prognostic factor for overall survival [45]. In 379 consecutive patients who underwent curative resection for pancreatic cancer, PLR was not associated with survival [20]. In 110 surgically treated pancreatic cancer patients, high PLR (≥150) was not associated with cancer-specific survival, as confirmed by p < 0.458 [25].

In a recent meta-analysis, published in 2018, the association between PLR and overall survival was not significant in surgically treated patients (HR = 1.45; 95% CI: 0.84–2.50; p = 0.19) although it was confirmed in the general group of 3028 patients (HR = 1.22; 95% CI: 1.09–1.36; p < 0.001) as well as in subgroups subjected to chemotherapy (HR = 1.18; 95% CI: 1.04–1.35; p = 0.01) or combined treatment (HR = 1.29; 95% CI: 1.07–1.57; p = 0.009). The difference might be attributable to the patient number, constituting only 228 surgically treated cases in contrast to 1313 patients who underwent chemotherapy and 1214—combined treatment [54]. However, another meta-analysis including eight studies, 1904 patients and 823 surgically treated cases, noted the same lack of association with overall survival shown by HR = 1.24; 95% CI: 0.95–1.62; p = 0.11 [55].

In 497 patients with locally advanced pancreatic cancer treated by chemoradiotherapy, elevated pre-treatment PLR (defined by the median as ≥149) was associated with worse 1-year survival rate and 1-year progression-free survival rate: 61.3 and 32.5% in contrast to those presenting with low PLR: 68.1% (p = 0.029) and 37.9% (p = 0.027), respectively [30]. Although in this study, both NLR and PLR were significantly associated with survival, greater biological differences were observed between NLR-defined groups (**Table 3**).

Gao et al. also noted that NLR is more sensitive than PLR in predicting treatment efficacy in unresectable pancreatic cancer [8]. In 88 pancreatic cancer patients treated by combination chemotherapy with gemcitabine and erlotinib, neither progression free survival nor overall survival was predicted by PLR while NLR had a prognostic role [58]. In 56 patients subjected to preoperative chemoradiotherapy and subsequent surgical treatment allowing to evaluate


Abbreviations: SIR, systemic inflammatory reaction; NLR, neutrophil to lymphocyte ratio; PLR, platelet to lymphocyte ratio.

**Table 3.** Prognostic estimated by PLR versus NLR in advanced pancreatic cancer [30].

the pathologic response, higher mean PLR was observed in poor versus good response group: 172.9 versus 147.3; however, the difference did not reach statistical significance. NLR was superior in this study [34]. In 261 patients with inoperable pancreatic cancer (including both metastatic and locally advanced cases), high PLR (≥150) was not associated with cancer-specific survival, as confirmed by p < 0.612 [25].

In contrast, in a small cohort of 66 patients diagnosed with advanced pancreatic cancer, only PLR (not NLR or other SIR parameters) was associated with survival [59]. In advanced pancreatic cancer, high PLR was a significant independent prognostic marker for shorter survival. The median survival was 4.0 versus 9.1 months in patients having PLR ≥ 200 versus PLR < 200 [31].

#### **3.2. PLR and metastatic spread**

Caucasians characterised by HR = 1.20; 95% CI: 0.90–1.62; p = 0.22 [54]. The same conclusion, pointing to significant role of PLR in Asia-based studies but not in those carried out in

Regarding surgically treated PDAC, prognostic role has been ascribed to PLR. In 131 surgically treated PDAC patients, PLR was an independent factor predicting overall and cancer free survival [56]. In a small group of 46 patients treated with pancreaticoduodenectomy for pancreatic cancer, high PLR ≥ 200 was associated with lower overall survival and was the only independent prognostic indicator contrasting with NLR [22]. In borderline resectable PDAC, high PLR (>225) was an independent factor predicting worse survival. The median survival

However, these findings have been challenged by a lot of contrary reports. PLR did not predict survival in 217 patients treated for resectable pancreatic cancer [28]. In even larger cohort of 442 pancreatic resections for cancer, there was no association between PLR and survival although NLR was an independent predictor of poor prognosis [21]. In 159 surgically treated patients, PLR lacked prognostic value in regard to overall survival; p = 0.463 although PLR was associated with lymph node metastasis that in turn was independent prognostic factor for overall survival [45]. In 379 consecutive patients who underwent curative resection for pancreatic cancer, PLR was not associated with survival [20]. In 110 surgically treated pancreatic cancer patients, high PLR (≥150) was not associated with cancer-specific survival, as

In a recent meta-analysis, published in 2018, the association between PLR and overall survival was not significant in surgically treated patients (HR = 1.45; 95% CI: 0.84–2.50; p = 0.19) although it was confirmed in the general group of 3028 patients (HR = 1.22; 95% CI: 1.09–1.36; p < 0.001) as well as in subgroups subjected to chemotherapy (HR = 1.18; 95% CI: 1.04–1.35; p = 0.01) or combined treatment (HR = 1.29; 95% CI: 1.07–1.57; p = 0.009). The difference might be attributable to the patient number, constituting only 228 surgically treated cases in contrast to 1313 patients who underwent chemotherapy and 1214—combined treatment [54]. However, another meta-analysis including eight studies, 1904 patients and 823 surgically treated cases, noted the same lack of association with overall survival shown by HR = 1.24;

In 497 patients with locally advanced pancreatic cancer treated by chemoradiotherapy, elevated pre-treatment PLR (defined by the median as ≥149) was associated with worse 1-year survival rate and 1-year progression-free survival rate: 61.3 and 32.5% in contrast to those presenting with low PLR: 68.1% (p = 0.029) and 37.9% (p = 0.027), respectively [30]. Although in this study, both NLR and PLR were significantly associated with survival, greater biologi-

Gao et al. also noted that NLR is more sensitive than PLR in predicting treatment efficacy in unresectable pancreatic cancer [8]. In 88 pancreatic cancer patients treated by combination chemotherapy with gemcitabine and erlotinib, neither progression free survival nor overall survival was predicted by PLR while NLR had a prognostic role [58]. In 56 patients subjected to preoperative chemoradiotherapy and subsequent surgical treatment allowing to evaluate

cal differences were observed between NLR-defined groups (**Table 3**).

was 10.2 versus 24.7 months in high versus low PLR groups; p = 0.003 [57].

Europe, was reported earlier by Song et al., [55].

14 Advances in Pancreatic Cancer

confirmed by p < 0.458 [25].

95% CI: 0.95–1.62; p = 0.11 [55].

Several reports indicate an important role of platelet activation in the metastatic cancer spread. PLR was significantly associated with lymph node metastasis; p < 0.001 [45]. Anti-platelet treatment, for example, by Clopidogrel, can inhibit the development of metastases [60].

#### **3.3. Diagnostic role of PLR in pancreatic tumours**

Differential diagnosis between chronic pancreatitis, presenting with tumour-like mass, and pancreatic ductal adenocarcinoma, can be difficult. Although inflammation is involved in both diseases, thrombocytosis and lymphopenia are more likely to occur in patients harbouring a malignant tumour. Comparing PLR in PDAC and inflammatory masses of pancreatic head, difference was revealed: PLR was 91 (interquartile range (IQR): 77.2–106.6) in patients diagnosed with pseudo-tumorous inflammation and 161.9 (IQR: 117.5–205.6) in PDAC. By ROC analysis, PLR reached area under curve (AUC) value of 88.8%, and the sensitivity and specificity were 79.4 and 92.6%, using cut-off at 113.5 [61]. Another study assessed the diagnostic value of PLR in the distinction between inflammatory pancreatic mass and PDAC in surgically treated patients. The sensitivity and specificity of PLR was comparable to CA 19-9, and combination of both improved the predictive value [62].

In mucinous cystic neoplasms, elevated PLR was shown to be significantly associated with presence of invasive carcinoma in 245 patients from Shanghai [47] and 318 patients from Singapore [48].
