Abstract
Objectives
Although systemic chemotherapy for pancreatic ductal adenocarcinoma (PDAC) has made progress, ensuring long-term survival remains difficult. There are several reports on the usefulness of neutrophil-to-lymphocyte ratio (NLR) in predicting the prognosis of PDAC, but few reports in systemic chemotherapy. We hereby investigated the usefulness of NLR in systemic chemotherapy for PDAC.
Materials and methods
A retrospective study was conducted on patients with advanced PDAC treated with first-line systemic chemotherapy. Cox regression hazards models were performed to analyze the association between baseline patient characteristics and the initial treatment response, and overall survival (OS).
Results
A total of 60 patients with PDAC were enrolled. At baseline, there were significant differences in NLR and carbohydrate antigen 19-9 (CA19-9), as well as the selection rate of combination chemotherapy, between patients with partial response or stable disease and those with progressive disease. Univariate and multivariate analysis showed that NLR < 3.10, combination chemotherapy, and CA19-9 < 1011 U/mL were significant and independent predictive factors of the initial treatment response. Meanwhile, NLR < 3.10 and combination chemotherapy were independently associated with longer OS. Moreover, OS was significantly prolonged in patients with NLR < 3.10, regardless of whether combination chemotherapy or monotherapy. Patients with NLR < 3.10 at baseline had a significantly higher conversion rate to third-line chemotherapy and a longer duration of total chemotherapy.
Conclusions
This study suggests that NLR may be a useful marker for predicting the initial treatment response to first-line chemotherapy and the prognosis for patients with advanced PDAC.
Keywords: Inflammation, lymphocyte, neutrophil, prognostic factor, treatment response
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is the fifth most common cancer worldwide and a highly aggressive malignancy [1]. Surgical resection is the only curative treatment for PDAC, but the resectability ratio at the first visit is only approximately 15–20% only [2]. Furthermore, the recurrence rate is very high even after complete resection, and the five-year survival rate is only 10–30% [3]. Systemic chemotherapy is an essential therapeutic approach to improve the prognosis in patients with unresectable and recurrent PDAC. In recent years, treatment outcomes have been improving due to the increasing number of available anticancer drugs. However, the median overall survival (OS) in patients with PDAC treated with systemic chemotherapy is still less than one year, which does not provide a sufficient prognostic improvement [4]. Therefore, there is a need to elucidate the prognostic predictors in systemic chemotherapy, since no established opinion exists at present.
Among the various reports on prognostic predictors in systemic chemotherapy for PDAC, carbohydrate antigen 19-9 (CA19-9), a typical tumour marker for PDAC, has been extensively investigated [5–7]. Reports have suggested that decreasing serum CA19-9 levels after initiation of systemic chemotherapy are associated with better prognosis [5,6]. Meanwhile, elevated baseline CA19-9 levels have been associated with worse prognosis, regardless of reduced CA19-9 levels during treatment [7]. Thus, serum CA19-9 levels may be useful as a prognostic predictor in systemic chemotherapy for PDAC. However, CA19-9 levels are not applicable to all patients with PDAC due to false negatives in Lewis-negative patients and false positives in patients with diabetes and cirrhosis [8]. Serum carcinoembryonic antigen (CEA) levels have also been reported to be associated with prognosis in systemic chemotherapy for PDAC [9], although to a lesser extent than CA19-9. Consequently, despite some sporadic reports on the correlation between tumour markers and the prognosis of patients with PDAC treated with systemic chemotherapy, their significance remains unclear.
Systemic inflammation plays a crucial role in the development and progression of several cancer types [10]. Even in PDAC, inflammation induces hypoxia, metabolic reprogramming, and immune suppression, and it is involved in tumour progression and metastasis [11]. The neutrophil-to-lymphocyte ratio (NLR) is a representative inflammation-based marker, and its correlation with the prognosis of several cancer types such as hepatocellular carcinoma [12] and colorectal cancer [13] has been reported. The usefulness of NLR as a prognostic factor has also been reported in patients with PDAC who underwent surgical resection [14,15]. Moreover, although several reports have focused on patients treated with chemoradiotherapy and best supportive care [16,17], few reports have focused on patients with advanced PDAC treated with systemic chemotherapy. Therefore, further investigation is required to determine the usefulness of NLR in those patients
Here, we aimed to evaluate the association between NLR at baseline and the initial treatment response or prognosis in systemic chemotherapy for advanced PDAC.
Materials and methods
Study population
This was a retrospective observational study. The study population consisted of patients with PDAC who were unresectable or had recurrence after complete resection, diagnosed pathologically or through imaging, and received first-line systemic chemotherapy at Hamamatsu University Hospital between April 2010 and July 2022. The study included 93 patients who were 18 years or older, while resectable cases were defined as those without distant metastasis and deemed completely resectable by imaging. Unresectable cases were defined by imaging as having distant metastasis or vascular invasion that could not be reconstructed. The exclusion criteria included cases in which systemic chemotherapy was discontinued within four weeks, cases in which the initial dose was less than 80%, cases treated with radiation therapy, cases that were resectable but received systemic chemotherapy for some reasons, cases in which the treatment response was not evaluated by imaging examination at 6 to 12 weeks after treatment initiation, and cases with missing laboratory values related to NLR. The remaining 60 patients were evaluated in this study. The patient selection process is summarized in Figure 1. This study was conducted with the approval of the ethics committee of Hamamatsu University Hospital (approval number 22-143). After approval by the ethical committee of Hamamatsu University Hospital, the requirement to obtain the consent from each patient was waived, but each patient was offered the opportunity to decline to participate in this study via an opt-out option.
Figure 1.
Flow diagram of the study.
Abbreviations: NLR, neutrophil-to-lymphocyte ratio; PDAC, pancreatic ductal adenocarcinoma.
Evaluations
The clinical and demographic characteristics of patients, tumour status, and laboratory data at baseline were collected from medical records at Hamamatsu University Hospital. The NLR was calculated as the total neutrophil count divided by total lymphocyte count. Treatment response was defined using response evaluation criteria in solid tumours (RECIST) version 1.1 [18], based on computed tomography (CT) imaging or magnetic resonance imaging (MRI) at 6 to 12 weeks. OS was defined as the time from the initiation of systemic chemotherapy until death from any cause, progression-free survival (PFS) was defined as the time from the initiation of systemic chemotherapy until the date of progression or death, and duration of chemotherapy was defined as the time from the initiation of systemic chemotherapy until the transition to best supportive care or death from any cause.
Statistical analyses
Data on patient characteristics are presented as numbers for categorical data, and medians and full ranges for continuous variables. The comparison of proportions for continuous variables between independent samples were evaluated using the Mann–Whitney’s U test or Student’s t-test. Categorical variables between independent samples were compared using Fisher’s exact tests. The predictive performances of NLR and CA19-9 levels were evaluated using the area under the receiver operating characteristic (AUROC) with 95% confidence intervals (CI). The best cut-off value was calculated using the Youden Index. OS and PFS were obtained using the Kaplan–Meier method, and significance was tested using the log-rank test. Multivariable Cox regression hazards models were performed to estimate the hazard ratio and identify the independent association of clinical parameters with the initial treatment response, OS, and PFS. All analyses were performed using EZR [19], which is a modified version of R commander designed to add statistical functions frequently used in biostatistics. A p-value of p <0.05 was considered statistically significant.
Results
Patient’s characteristics
The baseline patient characteristics are summarized in Table 1. Of the total patients, 41 were men (68%) and 19 women (32%). The median age of patients at initiation of first-line chemotherapy was 69.5 (46–84) years. The median follow-up time was 384 (44–1604) days. Most patients (58 cases, 97%) had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Tumours were located at the head of the pancreas in 37 patients (62%) and in the body or tail in 23 patients (38%). Distant metastases were present in 68% of patients, including the liver in 20 cases, peritoneal dissemination in 12 cases, lung in 9 cases, and distant lymph nodes in five cases. As for first-line chemotherapy, 23 cases (38%) were treated with gemcitabine plus nab-paclitaxel, 17 cases (29%) with FOLFIRINOX (a combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), eight cases (13%) with gemcitabine monotherapy, eight cases (13%) with S-1 monotherapy, three cases (5%) with gemcitabine plus S-1, and one case (2%) with gemcitabine plus erlotinib. Combination chemotherapy was selected as the first-line protocol in 44 cases (74%). Thirty-five patients (58%) were able to convert to second-line chemotherapy and 11 (18%) to third-line chemotherapy. The median values of NLR and CA19-9 were 2.98 and 471 U/mL, respectively.
Table 1.
Baseline characteristics.
| Variable | Results |
|---|---|
| Age [years] | 69.5 (46–84) |
| Male gender, n (%) | 41 (68) |
| Follow-up time [days] | 384 (44–1604) |
| ECOG-PS, n (%) | |
| 0 or 1 | 58 (97) |
| 2 | 2 (3) |
| Tumor stage of unresectable cases, n (%) | |
| Locally advanced | 19 (32) |
| Metastatic* | 41 (68) |
| Liver | 20 (33) |
| Peritoneal dissemination | 12 (20) |
| Lung | 9 (15) |
| Distant lymph nodes | 5 (8) |
| Tumor location, n (%) | |
| Head | 37 (62) |
| Body or tail | 23 (38) |
| First-line protocol, n (%) | |
| Gemcitabine plus nab-paclitaxel | 23 (38) |
| FOLFIRINOX | 17 (29) |
| Gemcitabine monotherapy | 8 (13) |
| S-1 monotherapy | 8 (13) |
| Gemcitabine plus S-1 | 3 (5) |
| Gemcitabine plus erlotinib | 1 (2) |
| Chemotherapy beyond first-line protocol, n (%) | |
| Second-line chemotherapy | 35 (58) |
| Third-line chemotherapy | 11 (18) |
| NLR | 2.98 (0.71–11.86) |
| CEA [ng/mL] | 4.6 (0.8–244.1) |
| CA19-9 [U/mL] | 471 (1–191801) |
Data for age, follow-up time, NLR, CEA, and CA19-9 are presented in medians and full ranges.
*The patient numbers are duplicated.
Abbreviations: CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; FOLFIRINOX, a combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; NLR, neutrophil-lymphocyte ratio.
Correlation between the initial treatment response to systemic chemotherapy and NLR
In the assessment of initial treatment response by imaging, partial response (PR) was observed in 20 cases (33%), stable disease (SD) in 20 cases (33%), progressive disease (PD) in 24 cases (40%), with no cases of complete response. The overall response rate and the disease control rate for first-line chemotherapy were 33% and 60%, respectively. Patients with PR and SD were classified as the response group, and those with PD were grouped as the non-response group in the initial evaluation of treatment response by imaging. The baseline patient characteristics of both groups are summarized in Table 2. The NLR was significantly lower in the response group (p < 0.05), whereas no significant differences were observed for the CEA and CA19-9 values between the two groups. As expected, OS and PFS were significantly longer in the response group (OS, p < 0.01; PFS, p < 0.01) (Figure 2A).
Table 2.
Baseline characteristics in the response group and the non-response group.
| Variable | Response group (n = 36) |
Non-response group (n = 24) |
p-value |
|---|---|---|---|
| Age [years] | 69.0 (46–84) | 69.5 (47–83) | 0.797 |
| Male gender, n (%) | 27 (75) | 15 (63) | 0.391 |
| ECOG-PS, n (%) | |||
| 0 or 1 | 36 (100) | 22 (92) | |
| 2 | 0 (0) | 2 (8) | 0.156 |
| Tumor stage of unresectable cases, n (%) | |||
| Locally advanced | 12 (33) | 7 (29) | 0.784 |
| Metastatic* | 24 (67) | 17 (71) | 0.784 |
| Liver | 11 (31) | 9 (38) | 0.590 |
| Peritoneal dissemination | 7 (19) | 5 (21) | 0.725 |
| Lung | 7 (19) | 2 (8) | 0.293 |
| Distant lymph nodes | 2 (6) | 3 (13) | 0.380 |
| Tumor location, n (%) | |||
| Head | 22 (61) | 15 (63) | |
| Body or tail | 14 (39) | 9 (37) | 1.000 |
| First-line protocol, n (%) | |||
| Combination chemotherapy | 31 (86) | 13 (54) | |
| Monotherapy | 5 (14) | 11 (46) | 0.008 |
| NLR | 2.70 (0.71–7.41) | 3.49 (0.72–11.86) | 0.048 |
| CEA [ng/mL] | 3.9 (0.8–46.0) | 5.6 (0.8–244.1) | 0.095 |
| CA19-9 [U/mL] | 258 (17–191801) | 1570 (1–49803) | 0.108 |
Data for age, NLR, CEA, and CA19-9 are presented in medians and full ranges.
*The patient numbers are duplicated. Statistically significant results are indicated with bold text in the p value column.
Abbreviations: CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; NLR, neutrophil-lymphocyte ratio.
Figure 2.
Kaplan–Meier analysis of OS and PFS in patients with advanced PDAC treated with systemic chemotherapy (A). ROC analysis of the baseline value of NLR and CA19-9 to predict the initial treatment response in first-line chemotherapy (B).
Abbreviations: AUROC, the area under the receiver operating characteristic; CA19-9, carbohydrate antigen 19-9; CI, confidence interval; HR, hazard ratio; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival; PFS, progression-free survival.
As shown in Figure 2B, NLR and CA19-9 demonstrated moderate ability to predict the initial treatment response beyond SD (AUROC: NLR, 0.652; CA19-9, 0.624). The cut-off values for NLR and CA19-9 were 3.10 and 1011 U/mL, respectively. Univariate analysis revealed that NLR < 3.10 (p < 0.05), combination chemotherapy (p < 0.01), and CA19-9 < 1011 U/mL (p < 0.05) were significantly associated with treatment response. Multivariate analysis revealed that NLR < 3.10 (p < 0.05), combination chemotherapy (p < 0.05), and CA19-9 < 1011 U/mL (p < 0.05) were independently associated with treatment response (Table 3).
Table 3.
Univariate and multivariate analyses for the initial treatment response in baseline characteristics.
| Univariate analysis |
Multivariate analysis |
||||||
|---|---|---|---|---|---|---|---|
| Variable | Categories | OR | 95% CI | p-value | OR | 95% CI | p-value |
| Age [years] | ≥ 65 versus < 65 | 0.67 | 0.21–2.12 | 0.573 | |||
| Sex | Male versus female | 1.80 | 0.59–5.51 | 0.391 | |||
| Stage | Metastatic versus locally advanced | 0.82 | 0.27–2.52 | 0.784 | |||
| Metastatic organ | Liver metastasis positive versus negative | 0.73 | 0.25–2.18 | 0.590 | |||
| Peritoneal dissemination positive versus negative | 1.69 | 0.39–7.31 | 0.725 | ||||
| Lung metastasis positive versus negative | 2.66 | 0.50–14.10 | 0.293 | ||||
| Tumor location | Head versus body or tail | 0.94 | 0.33–2.73 | 1.000 | |||
| First-line protocol | Combination therapy versus monotherapy | 5.25 | 1.52–18.10 | 0.008 | 6.39 | 1.53–26.70 | 0.011 |
| NLR | < 3.10 versus ≥ 3.10 | 4.00 | 1.34–12.00 | 0.017 | 4.88 | 1.35–17.70 | 0.016 |
| CEA [ng/mL] | < 4.4 versus ≥ 4.4 | 1.65 | 0.58–4.69 | 0.431 | |||
| CA19-9 [U/mL] | < 1011 versus ≥ 1011 | 4.33 | 1.44–13.00 | 0.015 | 4.70 | 1.32–16.70 | 0.017 |
Statistically significant results are indicated with bold text in the p value column. Abbreviations: CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CI, confidence interval; NLR, neutrophil-lymphocyte ratio; OR, odds ratio.
Survival analysis of advanced PDAC patients treated with systemic chemotherapy compared to NLR
Univariate and multivariate analyses were conducted to identify prognostic factors for OS. Univariate analysis revealed that NLR < 3.10 (Median 471 days, HR 0.43 [0.24–0.75], p < 0.01), combination chemotherapy (Median 426 days, HR 0.54 [0.29–1.00], p < 0.05), and CA19-9 < 1011 U/mL (Median 471 days, HR 0.57 [0.32–1.00], p < 0.05) were significantly associated with longer OS. Multivariate analysis revealed that NLR < 3.10 (HR 0.42 [0.24–0.75], p < 0.01) was independently associated with longer OS along with combination chemotherapy (HR 0.52 [0.28–0.98], p < 0.05) (Table 4). The survival probabilities for the lower NLR group (NLR < 3.10) and the higher NLR group (NLR ≥ 3.10) were 66% and 36% at 1 year, 28% and 7% at 2 years, and 6% and 4% at 3 years, respectively. For combination chemotherapy and monotherapy, the survival probabilities were 57% and 38% at 1 year, 21% and 13% at 2 years, and 7% and 0% at 3 years, respectively (Figure 3). Moreover, among the combination chemotherapy group, the survival probability in the lower NLR group was significantly longer than those in the higher NLR group (71% vs. 40% at 1 year; 29% vs. 10% at 2 years; and 8% vs. 5% at 3 years, p < 0.05) (Figure 4A). Similarly, the lower NLR group showed a significant prolongation of OS in the monotherapy group (50% vs. 25% at 1 year and 25% vs. 0% at 2 years, p < 0.05) (Figure 4B). Meanwhile, no factors other than NLR were significantly associated with PFS (Supplementary Table 1). Although there was no significant difference in the conversion rate to second-line chemotherapy, the conversion rate to third-line chemotherapy was significantly higher in the lower NLR group (p < 0.05) (Figure 5A). Additionally, the total duration of chemotherapy was significantly longer (p < 0.05) (Figure 5B). These results suggest that patients with advanced PDAC and lower NLR may experience a significant prolongation of PFS associated with a better initial treatment response to first-line chemotherapy and a longer duration of total chemotherapy, which may have contributed to a longer OS. Taken together, NLR may be a useful marker for predicting the initial treatment response and prognosis of systemic chemotherapy for patients with advanced PDAC.
Table 4.
Univariate and multivariate analyses of prognostic factors for overall survival.
| Univariate analysis |
Multivariate analysis |
||||||
|---|---|---|---|---|---|---|---|
| Variable | Categories | HR | 95% CI | p-value | HR | 95% CI | p-value |
| Age [years] | ≥ 65 versus < 65 | 1.27 | 0.69–2.34 | 0.448 | |||
| Sex | Male versus female | 0.77 | 0.42–1.40 | 0.387 | |||
| Stage | Metastatic versus locally advanced | 1.48 | 0.79–2.78 | 0.223 | |||
| Metastatic organ | Liver metastasis positive versus negative | 1.78 | 0.98–3.21 | 0.058 | |||
| Peritoneal dissemination positive versus negative | 1.02 | 0.47–2.19 | 0.965 | ||||
| Lung metastasis positive versus negative | 0.55 | 0.25–1.23 | 0.141 | ||||
| Tumor location | Head versus body or tail | 0.92 | 0.52–1.65 | 0.790 | |||
| First-line protocol | Combination therapy versus monotherapy | 0.54 | 0.29–1.00 | 0.045 | 0.52 | 0.28–0.98 | 0.044 |
| NLR | < 3.10 versus ≥ 3.10 | 0.43 | 0.24–0.75 | 0.003 | 0.42 | 0.24–0.75 | 0.003 |
| CEA [ng/mL] | < 4.4 versus ≥ 4.4 | 0.70 | 0.40–1.24 | 0.225 | |||
| CA19-9 [U/mL] | < 1011 versus ≥ 1011 | 0.57 | 0.32–1.00 | 0.048 | 0.68 | 0.38–1.21 | 0.189 |
Statistically significant results are indicated with bold text in the p value column. Abbreviations: CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CI, confidence interval; HR, hazard ratio; NLR, neutrophil-lymphocyte ratio.
Figure 3.
Kaplan–Meier analysis of OS stratified by the value of NLR (A) and chemotherapy regimen (B) in patients with advanced PDAC treated with systemic chemotherapy.
Abbreviations: CI, confidence interval; HR, hazard ratio; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival.
Figure 4.
Kaplan–Meier analysis of OS stratified by the value of NLR in patients with advanced PDAC treated with combination therapy (A) and monotherapy (B) at first-line chemotherapy.
Abbreviations: CI, confidence interval; HR, hazard ratio; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival.
Figure 5.
Conversion rate to second- and third-line chemotherapy stratified by the value of NLR (A). The total duration of systemic chemotherapy stratified by the value of NLR (B).
Lower NLR group, NLR < 3.10; Higher NLR group, NLR ≥ 3.10.
Abbreviations: NLR, neutrophil-to-lymphocyte ratio; N.S, not significant.
Discussion
In the present study, we evaluated the usefulness of NLR in patients with advanced PDAC treated with systemic chemotherapy and showed that NLR is a useful marker for predicting the initial treatment response and prognosis. Previous studies on prognostic factors in PDAC patients have mainly focused on surgically treated cases [20,21]. The difficulty of early detection and the frequent recurrence in resected cases are the main reasons for the poor prognosis of PDAC [22]. Therefore, examining prognostic factors in patients with PDAC treated with systemic chemotherapy, which is the main treatment for advanced PDAC, is crucial.
Systemic inflammation plays a key role in cancer progression [10]. NLR is a representative inflammation-based marker, and its usefulness as a prognostic predictor has been reported in various cancer types [12–15]. An increase in tumour-derived and infiltrating neutrophils, along with a decrease and dysfunction of lymphocytes caused by inflammatory cytokines, elevates NLR [23,24]. Increased levels of NLR in cancer promote tumour progression by enhancing inflammatory cytokines such as interleukin-2, interleukin-6 (IL-6), and tumour necrosis factor-α (TNFα) [25]. Additionally, a decrease in lymphocyte counts lead to a poor prognosis by providing an immunosuppressive condition [24]. In PDAC patients, several tumour-derived CXC motif chemokine families recruit neutrophils to the tumour microenvironment, promoting tumour cell survival and metastasis [26]. Therefore, while these factors are difficult to measure through general clinical practice, the ease of measuring NLR is its greatest advantage. Although there are several reports on the correlation between NLR and prognosis in patients with PDAC, most of them were focused on surgical resection [14,15], and only a few have been reported on systemic chemotherapy. The usefulness of NLR in neoadjuvant chemotherapy has been previously demonstrated [27,28]. However, only two reports similar to our study have investigated the usefulness of NLR for patients with advanced PDAC treated with systemic chemotherapy [29,30]. These reports demonstrated significant correlations between NLR and OS in gemcitabine-based regimens with an NLR cut-off value of 5 [29,30]. Similarly, in another report targeting surgically resected cases, the NLR cut-off value was set to 5 for analysis [31]. However, in these previous reports, the number of cases with NLR > 5 was only 16% [29] and 18% [30], respectively, with the higher NLR groups being in the minority. In our study, the number of cases with NLR > 5 was only 18%. Therefore, we performed an ROC analysis to predict the initial treatment response, and a cut-off value of 3.10 for NLR was determined. Using this cut-off value, we were able to demonstrate the correlation between NLR and prognosis without bias in the number of samples. Further investigation is required to determine the optimal cut-off value for NLR in patients with PDAC treated with systemic chemotherapy.
The present study revealed two new findings. First, NLR was found to be correlated with the initial treatment response to first-line chemotherapy in patients with PDAC, which to our knowledge, has not been previously reported. Previous studies on the correlation between NLR and systemic chemotherapy in patients with PDAC mainly focused on prognosis, and there is no study on the treatment response. In breast cancer, increased peripheral blood lymphocyte counts have been reported to elevate sensitivity to systemic chemotherapy by enhancing antitumor immunity [32], suggesting that systemic chemotherapy may be highly effective in patients with lower NLR. In addition, recent advances in systemic chemotherapy have led to increasing numbers of reports of conversion surgery in patients with PDAC who have responded to systemic chemotherapy [33]. Since surgical resection is the only curative treatment for patients with PDAC, aggressive chemotherapy aimed at conversion surgery may be considered in patients with low NLR.
Second, the lower NLR group had a longer duration of systemic chemotherapy with a higher conversion rate to subsequent treatments, suggesting that these factors may have contributed to the better prognosis. As described previously, mediators such as inflammatory cytokines, including IL-6 and TNFα, are involved in tumour progression [25] and also associated with cachexia [34] and performance status [35], which are important in determining whether systemic chemotherapy can be continued. Therefore, in patients with higher NLR, not only rapid tumour progression and resistance to systemic chemotherapy but also early discontinuation of systemic chemotherapy due to the deterioration of general condition may be associated with poor prognosis.
Regarding the conversion rate to subsequent treatment, 10 cases (17%) received third-line chemotherapy mainly using anticancer drugs that had not been used before the second-line treatment, and the lower NLR group showed a significantly higher conversion rate to third-line chemotherapy. Although second-line chemotherapy for patients with PDAC has been shown to improve prognosis [36], there is little evidence regarding third-line chemotherapy for PDAC due to the limited number of available anticancer drugs and the rapid progression of the disease. In contrast, it has been reported that the prognosis of colorectal cancer [37] and gastric cancer [38] is prolonged by using all available anticancer drugs. Whether a similar treatment strategy contributes to the prolongation of prognosis in PDAC remains an issue for further investigation.
This study had some limitations. First, this was a retrospective and a single-center study with a limited number of patients. Therefore, the results should be validated in a larger, multicentre prospective validation. Second, this study included various chemotherapy regimens, and the usefulness of NLR for each regimen has not been examined. Further studies are needed to evaluate the predictive value of NLR for specific chemotherapy regimens.
In conclusion, this study demonstrated that baseline NLR is associated with the initial treatment response to first-line chemotherapy and prognosis in patients with advanced PDAC treated with systemic chemotherapy. Our findings suggest that NLR may be a potential prognostic marker in patients with PDAC, but further studies in a larger population are required.
Supplementary Material
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing.
Funding Statement
No funding was received.
Ethical approval
This study was conducted in accordance with the guidelines of the Declaration of Helsinki and was approved by the ethics committee of Hamamatsu University Hospital (approval number 22-143). Each patient was offered the opportunity to decline to participate in this study via an opt-out option.
Consent form
The consent was waived off because of the retrospective nature of this study.
Authors contributions
KK (Kitsugi), KK (Kawata) and TS contributed to the conceptualization. KK (Kitsugi) was the major contributor to data curation, formal analysis, investigation, methodology, project administration and writing of original draft. KK (Kawata) and TS were supervisor of this study. KK (Kawata), HN, TC, KO, JI, ST, MY, TH. MU, MM, YM, MT, SF, RK, RM, SI, AM and TS reviewed this draft. All the authors have read and approved the final manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The data that support the findings of this study are available from the first author upon reasonable request.
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Data Availability Statement
The data that support the findings of this study are available from the first author upon reasonable request.