Ann Surg Oncol (2015) 22:670–676 DOI 10.1245/s10434-014-4021-y
ORIGINAL ARTICLE – PANCREATIC TUMORS
Blood Neutrophil–Lymphocyte Ratio Predicts Survival in Patients with Advanced Pancreatic Cancer Treated with Chemotherapy Guopei Luo, MD, PhD1,2,3, Meng Guo, PhD1,2,3, Zuqiang Liu, MD1,2,3, Zhiwen Xiao, MD1,2,3, Kaizhou Jin, MD, PhD1,2,3, Jiang Long, MD, PhD1,2,3, Liang Liu, MD, PhD1,2,3, Chen Liu, MD, PhD1,2,3, Jin Xu, MD, PhD1,2,3, Quanxing Ni, MD1,2,3, and Xianjun Yu, MD, PhD1,2,3 1
Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai, Peoples Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, Peoples Republic of China; 3Pancreatic Cancer Institute, Fudan University, Shanghai, Peoples Republic of China
ABSTRACT Background. Although a high neutrophil-to-lymphocyte ratio (NLR) has been reported to be a predictor of poor survival in patients with pancreatic cancers, its prognostic role in patients with advanced pancreatic cancer undergoing chemotherapy remains unclear. This study was performed to determine the prognostic role of NLR in patients with advanced pancreatic cancer undergoing chemotherapy. Methods. We retrospectively enrolled 403 patients undergoing chemotherapy for advanced pancreatic adenocarcinoma from 2002 to 2013. Univariate and multivariate analyses were performed to identify clinicopathological predictors of overall survival including baseline NLR (NLR before chemotherapy) and postchemotherapy NLR change (NLR change before and after one cycle of chemotherapy), using the Cox proportional hazards model. Clinicopathological characteristics related to baseline NLR and postchemotherapy NLR change were evaluated. Results. Univariate and multivariate analyses showed that both baseline NLR (NLR C 3.1 vs. NLR \ 3.1, hazard ratio [HR] = 1.42; P = 0.001) and postchemotherapy Guopei Luo, Meng Guo and Zuqiang Liu have contributed equally to the manuscript.
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-4021-y) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 2 December 2013; Published Online: 26 August 2014 X. Yu, MD, PhD e-mail: [email protected]
NLR change (NLR C 3.1 and increased vs. NLR \ 3.1 and decreased, HR = 2.39; P = 0.000) were independent prognostic factors in overall survival. NLR C 3.1 before chemotherapy and NLR postchemotherapy change were significantly correlated with distant metastasis, serum CA19-9 levels, and serum albumin levels. Conclusions. Baseline NLR and postchemotherapy NLR change may serve as potential biomarkers for overall survival in patients with advanced pancreatic cancer undergoing chemotherapy.
Pancreatic cancer is a highly devastating malignancy with a death rate nearly equal to its incidence.1–5 Curative resection for pancreatic cancer provides the best opportunity of prolonged survival.6 However, only 10–20 % of patients with pancreatic cancer are eligible for curative resection and actual 5-year survival after curative resection is approximately 20 %.6,7 Chemotherapy is one of the major treatments for pancreatic cancer.6 However, conventional chemotherapy has limited impact on disease course and the overall efficacy is unsatisfying.8 Therefore, it is important to identify a subgroup of patients who will benefit most from chemotherapy. Although various predictive factors for response to chemotherapy are identified in previous studies, there are still no promising predictive factors that enable a better risk stratification for chemotherapy in advanced pancreatic cancer patients.8 The neutrophil-to-lymphocyte ratio (NLR) was defined as the absolute neutrophil count divided by the absolute lymphocyte count, and was an inexpensive, widely available, and easily measurable predictor of systemic inflammation.9–15 Elevated pretreatment NLR was identified as an independent prognostic factor associated with
NLR and Pancreatic Cancer Patients Underwent Chemotherapy
poor outcome in various types of cancers, including colon cancer,15 gastric cancer,13 esophageal cancer,12 and breast cancer.9 Studies had indicated that an elevated NLR may correlate with a poor prognosis in patients with pancreatic cancer undergoing curative resection10,11,14 and bypass surgery.16 The pretreatment NLR was also found to be a biomarker for survival in patients who underwent systematic chemotherapy in various cancers, including colorectal cancer,17 malignant mesothelioma,18 non-small cell lung cancer,19 and gastric cancer.20 However, there is still no evidence determining the value of NLR in the assessment of suitable candidates for chemotherapy in patients with advanced pancreatic cancer. This study was performed to determine the association between the baseline NLR, or postchemotherapy NLR change, and the response to treatment and survival in a large cohort of patients with advanced pancreatic cancer. METHODS Study Design and Treatment Consecutive patients were retrospectively collected from the Shanghai Cancer Center, Fudan University between August 2002 and April 2013. Patients had histologic or cytologic evidence of locally advanced or metastatic adenocarcinoma of the pancreas. According to the American Joint Committee on Cancer (AJCC), 7th edition, TNM staging of pancreatic cancer, locally advanced cancer of the pancreas is defined as the tumor involves the celiac axis or the superior mesenteric artery without distant metastasis (unresectable primary tumor).21 Patients with prior curative resection and/or radiotherapy to primary tumors and major metastases were excluded from the study. All clinicopathological data were retrieved from the medical records of the Shanghai Cancer Center. In this study, most of the patients (74.9 %) underwent gemcitabine-based chemotherapy and a minority of the patients (25.1 %) underwent fluorine pyrimidines (fluorouracil, capecitabine, or S1 [tegafur, 5-chloro-2,4-dihydroxypyridine and oxonic acid]) treatment according to the newest edition of the National Comprehensive Cancer Network (NCCN) Guideline at the time. The regimen of gemcitabine alone was 1,000 mg/m2 (3 times per week followed by a 1-week rest for 6 cycles). The laboratory data, including neutrophil, lymphocyte, levels of serum albumin, and levels of serum CA19-9 were obtained before major treatments. The NLR was determined by the absolute neutrophil count divided by the absolute lymphocyte count. The timing of the NLR sample for the postchemotherapy was within 3 days before the next cycle of chemotherapy. The NLR change was
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calculated by the postchemotherapy NLR divided by the baseline NLR; an NLR increase was defined as C1 and an NLR decrease was defined as \1. The receiver operating characteristic (ROC) curve and area under the ROC curve were used to determine the best cut-off values for baseline NLR. Postchemotherapy NLR change was stratified according to baseline NLR and postchemotherapy variation. The postchemotherapy NLR change after two cycles of chemotherapy was also determined. A control group without chemotherapy was added to make a comparison. The baseline NLR and the NLR variation were also determined at approximately 4 weeks after the final diagnosis in the control group. The primary end point was overall survival. The patients were followed up until death or for at least 18 months. Follow-up information was updated in October 2013. Survival time was calculated from the date of final diagnosis to the date of the last follow-up or death. The study protocol was approved by the ethical committee of Shanghai Cancer Center, Fudan University. Informed consent was obtained from all patients participating in the study. Statistical Analysis Time-to-event variables were calculated by the Kaplan– Meier method. Arms stratified by baseline NLR and postchemotherapy NLR change were compared by using logrank tests. The HR with 95 % confidence intervals (CIs) was used as the primary estimate of the difference among the arms. The effects of potential prognostic factors were investigated by Cox regression using the STATA 12.0 statistical software package (StataCorp LP, College Station, TX). All variables with statistically significant prognostic value in univariate analysis were selected for further investigation in the multivariate analyses. The relationship between baseline NLR or postchemotherapy NLR changes and other clinicopathological characteristics was determined by parametric tests. A two-sided P \ 0.05 was taken for statistical significance. RESULTS The demographics of all patients are shown in Supplemental Table 1. The selected cut-off value of NLR was 3.1 by ROC curve (area under ROC curve, 0.66), and 48.1 % of patients had NLR levels higher than the cut-off value (Fig. 1). A multivariate Cox proportional hazards model including all variables significantly relevant to overall survival in univariable analysis was built to determine independent prognostic factors for overall survival. In the multivariate analysis, we found age C60 years (HR = 1.33; P = 0.007), metastatic
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NLR < 3.1 NLR ≥ 3.1 HR = 1.59, P = 0.000
0.00
0.25
0.50
0.75
A
1.00
672
0
5
10
209 194
136 78
59 28
1.00
NLR < 3.1 NLR ≥ 3.1
20
25
30
38 16
13 8
9 7
5 4
NLR < 3.1 ↓ HR = 1 NLR < 3.1 ↑ HR = 1.16, P = 0.349 NLR ≥ 3.1 ↓ HR = 1.41, P = 0.043
0.75
B
15
Time (month)
No. at risk
0.00
0.25
0.50
NLR ≥ 3.1 ↑ HR = 2.47, P = 0.000
0
5
10
NLR < 3.1 ↓ NLR < 3.1 ↑ NLR ≥ 3.1 ↓ NLR ≥ 3.1 ↑
15
20
25
30
5 8 5 2
3 6 4 2
2 3 4 0
Time (month)
No. at risk 64 127 82 84
50 78 44 26
21 34 14 7
12 24 9 3
FIG. 1 a Kaplan–Meier survival curves according to neutrophil-tolymphocyte ratio (NLR) \ 3.1 or NLR C 3.1 before chemotherapy. b Kaplan–Meier survival curves according to postchemotherapy NLR change after one cycle. HR hazard ratio, No number
diseases (HR = 1.63; P = 0.000), CA19-9 C 300 U/mL (HR = 1.30; P = 0.020), and baseline NLR C 3.1 (HR = 1.42; P = 0.001) (Table 1) as independent prognostic factors for overall survival. In the current study, 357 patients in the whole cohort had NLR information after chemotherapy. In the multivariate analysis, we found age C60 years (HR = 1.26; P = 0.038), metastatic diseases (HR = 1.33; P = 0.002), CA19-9 C 300 U/mL (HR = 1.50; P = 0.001), and NLR C 3.1 and increased (HR = 2.39; P = 0.000) (Table 2) as independent prognostic factors for overall survival. As shown in Fig. 2, the predicting value of the postchemotherapy NLR change after two cycles of chemotherapy was similar to that after one cycle of chemotherapy. In the subgroup analysis (gemcitabine and fluorine pyrimidines–based chemotherapy), both baseline NLR (NLR C 3.1 vs. NLR \ 3.1, gemcitabine-based, HR = 1.55; P = 0.000; fluorine pyrimidines–based, HR = 1.69; P = 0.009) and postchemotherapy NLR change (NLR C 3.1 and increased vs. NLR \ 3.1 and decreased, gemcitabine-based, HR = 2.36; P = 0.000; fluorine
pyrimidines–based, HR = 3.00; P = 0.003) were prognostic factors in overall survival. As shown in Fig. 3a, the baseline NLR could be used to predict the overall survival of the control group (NLR \ 3.1 vs. NLR C 3.1, HR = 1.72; P = 0.004). However, the predicting value of the NLR variation in the control group was inferior to that of postchemotherapy change (NLR C 3.1 and increased vs. NLR \ 3.1 and decreased, HR = 1.89; P = 0.191) (Fig. 3b) NLR change alone also plays an important role in predicting the survival of pancreatic cancer patients who underwent chemotherapy. The clinical value of NLR change had statistical significance in multivariate analysis (HR = 1.24; P = 0.053 in univariate analysis and HR = 1.38; P = 0.004 in multivariate analysis) (Supplemental Table 2). However, it was not better than that of prechemotherapy NLR (HR = 1.59; P = 0.000 in univariate analysis and HR = 1.42; P = 0.001 in multivariate analysis) (Table 1). We calculated the prognostic value of baseline NLR and postchemotherapy NLR changes separately for both the locally advanced group and the distant metastatic group. For the distant metastatic group, both baseline NLR and postchemotherapy NLR change had statistical significance of predicting value (baseline NLR, NLR C 3.1 vs. NLR \ 3.1, HR = 1.50; P = 0.001; postchemotherapy NLR change, NLR C 3.1 and increased vs. NLR \ 3.1 and decreased, HR = 2.56; P = 0.000). For the locally advanced group, although no statistical significance was found, both baseline NLR and postchemotherapy NLR change was associated with a trend of prognostic value (baseline NLR, NLR C 3.1 vs. NLR \ 3.1, HR = 1.38; P = 0.155; postchemotherapy NLR change, NLR C 3.1 and increased vs. NLR \ 3.1 and decreased, HR = 1.88; P = 0.057). The v2 was used to compare clinicopathological characteristics associated with baseline NLR (NLR \ 3.1 and NLR C 3.1) and postchemotherapy NLR changes (NLR increased and NLR decreased). Before chemotherapy, a NLR C 3.1 was statistically significant in correlation with distant metastasis (P = 0.000), serum CA19-9 levels (P = 0.001), and serum albumin levels (P = 0.001), but not with age, gender, tumor size, or Eastern Cooperative Oncology Group (ECOG) performance status (Supplemental Table 3). For postchemotherapy NLR changes, associations were also observed between postchemotherapy NLR changes and distant metastasis (P = 0.001), and serum CA19-9 levels (P = 0.008) and serum albumin levels (P = 0.014), but not age, gender, tumor size, or ECOG performance status (Supplemental Table 4). DISCUSSION NLR has been confirmed in various cancers regarding its role in predicting cancer development, therapeutic
NLR and Pancreatic Cancer Patients Underwent Chemotherapy
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TABLE 1 Univariate and multivariate analysis for overall survival of all patients using the Cox proportional hazards model including baseline NLR Characteristic
Parameter
No.
Univariate analysis
Multivariate analysis
HR
95 % CI
P
HR
95 % CI
P /
\60
194
1
/
/
1
/
C60
209
1.33
1.09–1.63
0.005
1.33
1.08–1.63
0.007
Gender
Male Female
251 152
1 0.82
/ 0.67–1.01
/ 0.055
1 0.87
/ 0.71–1.08
/ 0.210
Tumor size (cm)
\5
257
1
/
/
C5
146
1.04
0.85–1.28
0.708
Tumor location
Head
145
1
/
/
Others
258
1.16
0.94–1.43
0.164
Tumor spread
Locally
94
1
/
/
1
/
/
Distant
309
1.72
1.36–2.19
0.000
1.63
1.28–2.08
0.000
CA19-9 (U/ml)
\300
134
1
/
/
1
/
/
C300
269
1.49
1.20–1.85
0.000
1.30
1.04–1.62
0.020
Albumin (g/dl)
\3.1
39
1
/
/
C3.1
364
1 1.42
/ 1.15–1.74
/ 0.001
Age
ECOG
0.61–1.21
0.409
/
/
325
1.14
0.83–1.56
0.431
33
1.45
0.92–2.28
0.108
209 194
1 1.59
/ 1.30–1.94
/ 0.000
45
1 2 Baseline NLR
0.86 1
0
\3.1 C3.1
CA carbohydrate antigen, CI confidence interval, ECOG Eastern Cooperative Oncology Group performance status, HR hazard ratio, NLR neutrophil-to-lymphocyte ratio, No. number, / no value
response, and prognosis.9–15 In this study, we demonstrated that baseline NLR was an independent prognostic predictor for patients with advanced pancreatic cancer undergoing chemotherapy, even after adjusting for potential confounding factors. Moreover, compared with patients with a baseline NLR \ 3.1 and decreased after chemotherapy, the HR for patients with a baseline NLR C 3.1 and elevated after chemotherapy was 2.47, indicating that an elevated baseline NLR with postchemotherapy NLR increase was the strongest prognostic factor for patients undergoing chemotherapy. These markers will help identify potential advanced pancreatic cancer candidates who will and will not benefit from chemotherapy. The postchemotherapy NLR change after two cycles of chemotherapy also had value in predicting prognosis. Nonetheless, given the dismal prognosis of patients with advanced pancreatic cancer, it may be better if we know the response to chemotherapy in a short time window (e.g., a cycle) so that we can make a timely change. The observation that the predicting value of the NLR variation in the control group was inferior to that of postchemotherapy change indicates the prognostic significance of the postchemotherapy NLR change for patients who underwent chemotherapy. NLR is an important and widely available marker of systematic inflammation and is related to various
biochemical and cellular activities.9–15 The importance of inflammatory response to pancreatic cancer has been well recognized in recent years.1–4 Inflammatory cells surrounding cancer cells have been confirmed to contribute an important role in pancreatic cancer initiation and prognosis.1–4 For example, Ino et al.22 systematically determined tumor-infiltrating immune/inflammatory cells in pancreatic cancer and analyzed their clinicopathological impact. They found that higher levels of neutrophils or the ratio of Tregs to CD4?T (%Treg) were significantly associated with poorer prognosis, whereas higher levels of tumor-infiltrating CD4?T or CD8?T were significantly associated with better prognosis.22 In another study, Fogar et al.23 confirmed that lower total lymphocyte counts in blood for patients with pancreatic cancer was an index of adverse prognosis. K-Ras activating mutations are the most common genetic alterations in pancreatic cancer1,4 and activation of K-Ras/RAF/ MEK signaling can stimulate neutrophils accumulation followed by intensive inflammatory reaction.24 The NLR offers important prognostic information for patients with operable and inoperable pancreatic cancer.10,11,14,16,25 For example, Garcea et al.11 identified 74 consecutive patients who underwent pancreaticoduodenectomy for pancreatic cancer and showed that a NLR [ 5 presented a disease-free survival of 12 months compared with
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TABLE 2 Univariate and multivariate analysis for overall survival of all patients using the Cox proportional hazards model including baseline NLR and postchemotherapy NLR change Characteristic
Parameter
No.
Univariate analysis
Multivariate analysis
HR
95 % CI
P
HR
95 % CI
P /
\60
174
1
/
/
1
/
C60
183
1.36
1.10–1.69
0.004
1.26
1.01–1.57
0.038
Gender
Male Female
223 134
1 0.79
/ 0.63–0.99
/ 0.035
1 0.84
/ 0.68–1.06
/ 0.137
Tumor size (cm)
\5
225
1
/
/
C5
132
1.01
0.81–1.26
0.940
Tumor location
Head
127
1
/
/
Others
230
1.16
0.93–1.45
0.179
Tumor spread
Locally
82
1
/
/
1
/
/
distant
275
1.61
1.24–2.08
0.000
1.53
1.18–1.99
0.002
CA19-9 (U/ml)
\300
120
1
/
/
1
/
/
C300
237
1.61
1.28–2.02
0.000
1.50
1.18–1.91
0.001
Albumin (g/dl)
\3.1
33
1
/
/
C3.1
324
Age
ECOG
NLR change
0.93
0.64–1.35
0.719
1
/
/
284
1.11
0.80–1.54
0.549
0
42
1 2
31
1.66
1.04–2.65
0.035
\3.1 ; \3.1 :
64 127
1 1.16
/ 0.85–1.57
/ 0.349
1 1.23
/ 0.90–1.67
/ 0.198
C3.1 ;
82
1.41
1.01–1.97
0.043
1.23
0.87–1.72
0.242
C3.1 :
84
2.47
1.77–3.45
0.000
2.39
1.71–3.34
0.000
Forty-six patients in the whole cohort had no neutrophil-to-lymphocyte ratio (NLR) information after chemotherapy
1.00
CA carbohydrate antigen, CI confidence interval, ECOG Eastern Cooperative Oncology Group performance status, HR hazard ratio, ; decreased, : increased, / no value
0.75
NLR < 3.1 ↓ HR = 1 NLR < 3.1 ↑ HR = 1.31, P = 0.141 NLR ≥ 3.1 ↓ HR = 1.49, P = 0.053
0.00
0.25
0.50
NLR ≥ 3.1 ↑ HR = 2.24, P = 0.000
0 No. at risk NLR < 3.1 ↓ NLR < 3.1 ↑ NLR ≥ 3.1 ↓ NLR ≥ 3.1 ↑
5
10
15
20
25
30
5 8 3 4
4 5 3 4
2 3 2 2
Time (month) 45 123 59 70
37 79 38 26
16 35 11 7
10 24 5 6
FIG. 2 Kaplan–Meier survival curves according to baseline neutrophil-to-lymphocyte ratio (NLR) and postchemotherapy NLR change after two cycles of chemotherapy. HR hazard ratio, No. number
52 months for those patients with NLR \ 5 (P \ 0.001). In another study, Sugiura et al.16 analyzed 83 patients with advanced pancreatic cancer and gastric outlet obstruction who underwent gastroenterostomy, and demonstrated that a
preoperative NLR C 4 was significant for independent prognostic factors. However, further evidence is needed to confirm the role of NLR in patients with advanced pancreatic cancer undergoing chemotherapy, which has clinical significance for more than 80 % of patients with pancreatic cancer who are not candidates for curative resection.6,7 NLR could predict the clinical outcomes in cancer patients treated with chemotherapy.17–20 For example, Yao et al.19 retrospectively reviewed 182 patients with advanced non-small cell lung cancer who were treated with first-line platinum-based chemotherapy and showed that a high pretreatment NLR (HR = 1.761; P = 0.020 for overall survival) was an independent prognostic factor. In another study, Lee et al.20 analyzed 174 patients with advanced gastric cancer who were treated with chemotherapy and found that NLR and changes of NLR after one cycle of chemotherapy are independent prognostic factors for overall survival. In this study, baseline NLR and postchemotherapy NLR change after one cycle of chemotherapy are independent prognostic factors for overall survival for advanced pancreatic cancer patients undergoing chemotherapy.
675
NLR < 3.1 NLR ≥ 3.1 HR = 1.72, P = 0.004
0.00
0.25
0.50
0.75
A
1.00
NLR and Pancreatic Cancer Patients Underwent Chemotherapy
0
5
10
48 77
19 20
1.00
NLR < 3.1 NLR < 3.1
20
25
30
8 6
4 5
2 2
2 1
2 1
NLR < 3.1 ↓ HR = 1 NLR < 3.1 ↑ HR = 1.99, P = 0.976
0.75
B
15
Time (month)
No. at risk
0.00
0.25
0.50
NLR ≥ 3.1 ↓ HR = 1.80, P = 0.675 NLR ≥ 3.1 ↑ HR = 1.89, P = 0.191
0
5
10
NLR < 3.1 ↓ NLR < 3.1 ↑ NLR ≥ 3.1 ↓ NLR ≥ 3.1 ↑
15
20
25
30
0 0 2 0
0 0 2 0
0 0 2 0
Time (month)
No. at risk 5 29 16 31
2 9 7 5
0 4 4 1
0 1 3 1
FIG. 3 a Kaplan–Meier survival curves according to baseline neutrophil-to-lymphocyte ratio (NLR). b Kaplan–Meier survival curves according to NLR change compared to baseline and after 1 month. HR hazard ratio, No. number
In this study, both baseline NLR and postchemotherapy NLR changes were found to be related to tumor spread and serum CA19-9 levels. High serum CA19-9 levels and tumor spread were demonstrated to be associated with a poor prognosis and serum CA19-9 levels correlated with tumor burden and stage.24–27 The previous study has showed that higher tumor stage was associated with elevated NLR in non-small cell lung cancer (P = 0.019), which was confirmed in the current study.28 Although a higher NLR was associated with an advanced stage and serum CA19-9 levels, NLR remained an independent predictor of prognosis in the adjusted models by multivariate analysis. Therefore, the association between higher NLR and prognosis was not solely explained by the advanced stage of cancer.28 As mentioned above, the NLR is a ratio and it may change if either the number of neutrophils or lymphocytes changes. Several well-known factors including chemotherapy toxicity, chronic inflammatory diseases, granulocyte colony-stimulating factor administration, pathogenic inflammation,29 and
other diseases30,31 could induce the number of neutrophils and/or lymphocytes changes, which may complicate the use of NLR. Therefore, we need to keep these conditions in mind in clinical practice. The major limitation of the study is the retrospective finding on the basis of a single institution. Nonetheless, this is the first study showing that NLR is an independent indicator of prognosis for patients with pancreatic cancer undergoing chemotherapy. In addition, this is a relatively large-sized sample for this study compared with other related studies. Moreover, we not only determined the role of prechemotherapy NLR, but also NLR change after one cycle of chemotherapy to the prognosis of patients with advanced pancreatic cancer. Nonetheless, NLR is affected by internal and external factors, including acute and chronic infection and lifestyle-related habits.32 Further multicentric prospective studies are needed to optimize NLR cut-off level and determine its strength and shortages. In conclusion, both baseline NLR and postchemotherapy NLR changes are identified as independent prognostic predictors for patients with advanced pancreatic cancer undergoing chemotherapy. These factors could be used to predict therapeutic response to chemotherapy for these patients. ACKNOWLEDGMENT This study was supported in part by the Sino-German Center (GZ857), by the Science Foundation of Shanghai (13ZR1407500), by the Shanghai Rising Star Program (12QH1400600, 14QA1400900), by the Fudan University Young Investigator-promoting program (20520133403), and by the National Science Foundation of China (Grant No. 81101807, No. 81001058, No. 81372649, No. 81372653, and No. 81172276). DISCLOSURE The authors declare no potential conflicts of interest in this study.
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31.
32.
with first-line platinum-based chemotherapy. Cancer Immunol Immunother. 2013;62:471–9. Lee S, Oh SY, Kim SH, et al. Prognostic significance of neutrophil lymphocyte ratio and platelet lymphocyte ratio in advanced gastric cancer patients treated with FOLFOX chemotherapy. BMC Cancer. 2013;13:350. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–4. Ino Y, Yamazaki-Itoh R, Shimada K, et al. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer. 2013;108:914–23. Fogar P, Sperti C, Basso D, et al. Decreased total lymphocyte counts in pancreatic cancer: an index of adverse outcome. Pancreas. 2006;32:22–8. Ji H, Houghton AM, Mariani TJ, et al. K-ras activation generates an inflammatory response in lung tumors. Oncogene. 2006;25:2105–12. Aliustaoglu M, Bilici A, Seker M, et al. The association of pretreatment peripheral blood markers with survival in patients with pancreatic cancer. Hepatogastroenterology. 2010;57:640–5. Luo G, Xiao Z, Long J, et al. CA125 is superior to CA19-9 in predicting the resectability of pancreatic cancer. J Gastrointest Surg. 2013;17:2092–8. Ferrone CR, Finkelstein DM, Thayer SP, Muzikansky A, Fernandez-delCastillo C, Warshaw AL. Perioperative CA19-9 levels can predict stage and survival in patients with resectable pancreatic adenocarcinoma. J Clin Oncol. 2006;24:2897–902. Sarraf KM, Belcher E, Raevsky E, Nicholson AG, Goldstraw P, Lim E. Neutrophil/lymphocyte ratio and its association with survival after complete resection in non-small cell lung cancer. J Thorac Cardiovasc Surg. 2009;137:425–8. Farah R, Khamisy-Farah R. Association of neutrophil to lymphocyte ratio with presence and severity of gastritis due to Helicobacter pylori infection. J Clin Lab Anal. 2014;28:219–23. Kaya H, Ertas F, Islamoglu Y, et al. Association between neutrophil to lymphocyte ratio and severity of coronary artery disease. Clin Appl Thromb Hemost. 2014;20:50–4. Sefil F, Ulutas KT, Dokuyucu R, et al. Investigation of neutrophil lymphocyte ratio and blood glucose regulation in patients with type 2 diabetes mellitus. J Int Med Res. 2014;42:581–8. Buyukkaya E, Karakas MF, Karakas E, et al. Correlation of neutrophil to lymphocyte ratio with the presence and severity of metabolic syndrome. Clin Appl Thromb Hemost. 2012;20:159– 63.
ORIGINAL ARTICLE – PANCREATIC TUMORS
Blood Neutrophil–Lymphocyte Ratio Predicts Survival in Patients with Advanced Pancreatic Cancer Treated with Chemotherapy Guopei Luo, MD, PhD1,2,3, Meng Guo, PhD1,2,3, Zuqiang Liu, MD1,2,3, Zhiwen Xiao, MD1,2,3, Kaizhou Jin, MD, PhD1,2,3, Jiang Long, MD, PhD1,2,3, Liang Liu, MD, PhD1,2,3, Chen Liu, MD, PhD1,2,3, Jin Xu, MD, PhD1,2,3, Quanxing Ni, MD1,2,3, and Xianjun Yu, MD, PhD1,2,3 1
Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai, Peoples Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, Peoples Republic of China; 3Pancreatic Cancer Institute, Fudan University, Shanghai, Peoples Republic of China
ABSTRACT Background. Although a high neutrophil-to-lymphocyte ratio (NLR) has been reported to be a predictor of poor survival in patients with pancreatic cancers, its prognostic role in patients with advanced pancreatic cancer undergoing chemotherapy remains unclear. This study was performed to determine the prognostic role of NLR in patients with advanced pancreatic cancer undergoing chemotherapy. Methods. We retrospectively enrolled 403 patients undergoing chemotherapy for advanced pancreatic adenocarcinoma from 2002 to 2013. Univariate and multivariate analyses were performed to identify clinicopathological predictors of overall survival including baseline NLR (NLR before chemotherapy) and postchemotherapy NLR change (NLR change before and after one cycle of chemotherapy), using the Cox proportional hazards model. Clinicopathological characteristics related to baseline NLR and postchemotherapy NLR change were evaluated. Results. Univariate and multivariate analyses showed that both baseline NLR (NLR C 3.1 vs. NLR \ 3.1, hazard ratio [HR] = 1.42; P = 0.001) and postchemotherapy Guopei Luo, Meng Guo and Zuqiang Liu have contributed equally to the manuscript.
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-4021-y) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 2 December 2013; Published Online: 26 August 2014 X. Yu, MD, PhD e-mail: [email protected]
NLR change (NLR C 3.1 and increased vs. NLR \ 3.1 and decreased, HR = 2.39; P = 0.000) were independent prognostic factors in overall survival. NLR C 3.1 before chemotherapy and NLR postchemotherapy change were significantly correlated with distant metastasis, serum CA19-9 levels, and serum albumin levels. Conclusions. Baseline NLR and postchemotherapy NLR change may serve as potential biomarkers for overall survival in patients with advanced pancreatic cancer undergoing chemotherapy.
Pancreatic cancer is a highly devastating malignancy with a death rate nearly equal to its incidence.1–5 Curative resection for pancreatic cancer provides the best opportunity of prolonged survival.6 However, only 10–20 % of patients with pancreatic cancer are eligible for curative resection and actual 5-year survival after curative resection is approximately 20 %.6,7 Chemotherapy is one of the major treatments for pancreatic cancer.6 However, conventional chemotherapy has limited impact on disease course and the overall efficacy is unsatisfying.8 Therefore, it is important to identify a subgroup of patients who will benefit most from chemotherapy. Although various predictive factors for response to chemotherapy are identified in previous studies, there are still no promising predictive factors that enable a better risk stratification for chemotherapy in advanced pancreatic cancer patients.8 The neutrophil-to-lymphocyte ratio (NLR) was defined as the absolute neutrophil count divided by the absolute lymphocyte count, and was an inexpensive, widely available, and easily measurable predictor of systemic inflammation.9–15 Elevated pretreatment NLR was identified as an independent prognostic factor associated with
NLR and Pancreatic Cancer Patients Underwent Chemotherapy
poor outcome in various types of cancers, including colon cancer,15 gastric cancer,13 esophageal cancer,12 and breast cancer.9 Studies had indicated that an elevated NLR may correlate with a poor prognosis in patients with pancreatic cancer undergoing curative resection10,11,14 and bypass surgery.16 The pretreatment NLR was also found to be a biomarker for survival in patients who underwent systematic chemotherapy in various cancers, including colorectal cancer,17 malignant mesothelioma,18 non-small cell lung cancer,19 and gastric cancer.20 However, there is still no evidence determining the value of NLR in the assessment of suitable candidates for chemotherapy in patients with advanced pancreatic cancer. This study was performed to determine the association between the baseline NLR, or postchemotherapy NLR change, and the response to treatment and survival in a large cohort of patients with advanced pancreatic cancer. METHODS Study Design and Treatment Consecutive patients were retrospectively collected from the Shanghai Cancer Center, Fudan University between August 2002 and April 2013. Patients had histologic or cytologic evidence of locally advanced or metastatic adenocarcinoma of the pancreas. According to the American Joint Committee on Cancer (AJCC), 7th edition, TNM staging of pancreatic cancer, locally advanced cancer of the pancreas is defined as the tumor involves the celiac axis or the superior mesenteric artery without distant metastasis (unresectable primary tumor).21 Patients with prior curative resection and/or radiotherapy to primary tumors and major metastases were excluded from the study. All clinicopathological data were retrieved from the medical records of the Shanghai Cancer Center. In this study, most of the patients (74.9 %) underwent gemcitabine-based chemotherapy and a minority of the patients (25.1 %) underwent fluorine pyrimidines (fluorouracil, capecitabine, or S1 [tegafur, 5-chloro-2,4-dihydroxypyridine and oxonic acid]) treatment according to the newest edition of the National Comprehensive Cancer Network (NCCN) Guideline at the time. The regimen of gemcitabine alone was 1,000 mg/m2 (3 times per week followed by a 1-week rest for 6 cycles). The laboratory data, including neutrophil, lymphocyte, levels of serum albumin, and levels of serum CA19-9 were obtained before major treatments. The NLR was determined by the absolute neutrophil count divided by the absolute lymphocyte count. The timing of the NLR sample for the postchemotherapy was within 3 days before the next cycle of chemotherapy. The NLR change was
671
calculated by the postchemotherapy NLR divided by the baseline NLR; an NLR increase was defined as C1 and an NLR decrease was defined as \1. The receiver operating characteristic (ROC) curve and area under the ROC curve were used to determine the best cut-off values for baseline NLR. Postchemotherapy NLR change was stratified according to baseline NLR and postchemotherapy variation. The postchemotherapy NLR change after two cycles of chemotherapy was also determined. A control group without chemotherapy was added to make a comparison. The baseline NLR and the NLR variation were also determined at approximately 4 weeks after the final diagnosis in the control group. The primary end point was overall survival. The patients were followed up until death or for at least 18 months. Follow-up information was updated in October 2013. Survival time was calculated from the date of final diagnosis to the date of the last follow-up or death. The study protocol was approved by the ethical committee of Shanghai Cancer Center, Fudan University. Informed consent was obtained from all patients participating in the study. Statistical Analysis Time-to-event variables were calculated by the Kaplan– Meier method. Arms stratified by baseline NLR and postchemotherapy NLR change were compared by using logrank tests. The HR with 95 % confidence intervals (CIs) was used as the primary estimate of the difference among the arms. The effects of potential prognostic factors were investigated by Cox regression using the STATA 12.0 statistical software package (StataCorp LP, College Station, TX). All variables with statistically significant prognostic value in univariate analysis were selected for further investigation in the multivariate analyses. The relationship between baseline NLR or postchemotherapy NLR changes and other clinicopathological characteristics was determined by parametric tests. A two-sided P \ 0.05 was taken for statistical significance. RESULTS The demographics of all patients are shown in Supplemental Table 1. The selected cut-off value of NLR was 3.1 by ROC curve (area under ROC curve, 0.66), and 48.1 % of patients had NLR levels higher than the cut-off value (Fig. 1). A multivariate Cox proportional hazards model including all variables significantly relevant to overall survival in univariable analysis was built to determine independent prognostic factors for overall survival. In the multivariate analysis, we found age C60 years (HR = 1.33; P = 0.007), metastatic
G. Luo et al.
NLR < 3.1 NLR ≥ 3.1 HR = 1.59, P = 0.000
0.00
0.25
0.50
0.75
A
1.00
672
0
5
10
209 194
136 78
59 28
1.00
NLR < 3.1 NLR ≥ 3.1
20
25
30
38 16
13 8
9 7
5 4
NLR < 3.1 ↓ HR = 1 NLR < 3.1 ↑ HR = 1.16, P = 0.349 NLR ≥ 3.1 ↓ HR = 1.41, P = 0.043
0.75
B
15
Time (month)
No. at risk
0.00
0.25
0.50
NLR ≥ 3.1 ↑ HR = 2.47, P = 0.000
0
5
10
NLR < 3.1 ↓ NLR < 3.1 ↑ NLR ≥ 3.1 ↓ NLR ≥ 3.1 ↑
15
20
25
30
5 8 5 2
3 6 4 2
2 3 4 0
Time (month)
No. at risk 64 127 82 84
50 78 44 26
21 34 14 7
12 24 9 3
FIG. 1 a Kaplan–Meier survival curves according to neutrophil-tolymphocyte ratio (NLR) \ 3.1 or NLR C 3.1 before chemotherapy. b Kaplan–Meier survival curves according to postchemotherapy NLR change after one cycle. HR hazard ratio, No number
diseases (HR = 1.63; P = 0.000), CA19-9 C 300 U/mL (HR = 1.30; P = 0.020), and baseline NLR C 3.1 (HR = 1.42; P = 0.001) (Table 1) as independent prognostic factors for overall survival. In the current study, 357 patients in the whole cohort had NLR information after chemotherapy. In the multivariate analysis, we found age C60 years (HR = 1.26; P = 0.038), metastatic diseases (HR = 1.33; P = 0.002), CA19-9 C 300 U/mL (HR = 1.50; P = 0.001), and NLR C 3.1 and increased (HR = 2.39; P = 0.000) (Table 2) as independent prognostic factors for overall survival. As shown in Fig. 2, the predicting value of the postchemotherapy NLR change after two cycles of chemotherapy was similar to that after one cycle of chemotherapy. In the subgroup analysis (gemcitabine and fluorine pyrimidines–based chemotherapy), both baseline NLR (NLR C 3.1 vs. NLR \ 3.1, gemcitabine-based, HR = 1.55; P = 0.000; fluorine pyrimidines–based, HR = 1.69; P = 0.009) and postchemotherapy NLR change (NLR C 3.1 and increased vs. NLR \ 3.1 and decreased, gemcitabine-based, HR = 2.36; P = 0.000; fluorine
pyrimidines–based, HR = 3.00; P = 0.003) were prognostic factors in overall survival. As shown in Fig. 3a, the baseline NLR could be used to predict the overall survival of the control group (NLR \ 3.1 vs. NLR C 3.1, HR = 1.72; P = 0.004). However, the predicting value of the NLR variation in the control group was inferior to that of postchemotherapy change (NLR C 3.1 and increased vs. NLR \ 3.1 and decreased, HR = 1.89; P = 0.191) (Fig. 3b) NLR change alone also plays an important role in predicting the survival of pancreatic cancer patients who underwent chemotherapy. The clinical value of NLR change had statistical significance in multivariate analysis (HR = 1.24; P = 0.053 in univariate analysis and HR = 1.38; P = 0.004 in multivariate analysis) (Supplemental Table 2). However, it was not better than that of prechemotherapy NLR (HR = 1.59; P = 0.000 in univariate analysis and HR = 1.42; P = 0.001 in multivariate analysis) (Table 1). We calculated the prognostic value of baseline NLR and postchemotherapy NLR changes separately for both the locally advanced group and the distant metastatic group. For the distant metastatic group, both baseline NLR and postchemotherapy NLR change had statistical significance of predicting value (baseline NLR, NLR C 3.1 vs. NLR \ 3.1, HR = 1.50; P = 0.001; postchemotherapy NLR change, NLR C 3.1 and increased vs. NLR \ 3.1 and decreased, HR = 2.56; P = 0.000). For the locally advanced group, although no statistical significance was found, both baseline NLR and postchemotherapy NLR change was associated with a trend of prognostic value (baseline NLR, NLR C 3.1 vs. NLR \ 3.1, HR = 1.38; P = 0.155; postchemotherapy NLR change, NLR C 3.1 and increased vs. NLR \ 3.1 and decreased, HR = 1.88; P = 0.057). The v2 was used to compare clinicopathological characteristics associated with baseline NLR (NLR \ 3.1 and NLR C 3.1) and postchemotherapy NLR changes (NLR increased and NLR decreased). Before chemotherapy, a NLR C 3.1 was statistically significant in correlation with distant metastasis (P = 0.000), serum CA19-9 levels (P = 0.001), and serum albumin levels (P = 0.001), but not with age, gender, tumor size, or Eastern Cooperative Oncology Group (ECOG) performance status (Supplemental Table 3). For postchemotherapy NLR changes, associations were also observed between postchemotherapy NLR changes and distant metastasis (P = 0.001), and serum CA19-9 levels (P = 0.008) and serum albumin levels (P = 0.014), but not age, gender, tumor size, or ECOG performance status (Supplemental Table 4). DISCUSSION NLR has been confirmed in various cancers regarding its role in predicting cancer development, therapeutic
NLR and Pancreatic Cancer Patients Underwent Chemotherapy
673
TABLE 1 Univariate and multivariate analysis for overall survival of all patients using the Cox proportional hazards model including baseline NLR Characteristic
Parameter
No.
Univariate analysis
Multivariate analysis
HR
95 % CI
P
HR
95 % CI
P /
\60
194
1
/
/
1
/
C60
209
1.33
1.09–1.63
0.005
1.33
1.08–1.63
0.007
Gender
Male Female
251 152
1 0.82
/ 0.67–1.01
/ 0.055
1 0.87
/ 0.71–1.08
/ 0.210
Tumor size (cm)
\5
257
1
/
/
C5
146
1.04
0.85–1.28
0.708
Tumor location
Head
145
1
/
/
Others
258
1.16
0.94–1.43
0.164
Tumor spread
Locally
94
1
/
/
1
/
/
Distant
309
1.72
1.36–2.19
0.000
1.63
1.28–2.08
0.000
CA19-9 (U/ml)
\300
134
1
/
/
1
/
/
C300
269
1.49
1.20–1.85
0.000
1.30
1.04–1.62
0.020
Albumin (g/dl)
\3.1
39
1
/
/
C3.1
364
1 1.42
/ 1.15–1.74
/ 0.001
Age
ECOG
0.61–1.21
0.409
/
/
325
1.14
0.83–1.56
0.431
33
1.45
0.92–2.28
0.108
209 194
1 1.59
/ 1.30–1.94
/ 0.000
45
1 2 Baseline NLR
0.86 1
0
\3.1 C3.1
CA carbohydrate antigen, CI confidence interval, ECOG Eastern Cooperative Oncology Group performance status, HR hazard ratio, NLR neutrophil-to-lymphocyte ratio, No. number, / no value
response, and prognosis.9–15 In this study, we demonstrated that baseline NLR was an independent prognostic predictor for patients with advanced pancreatic cancer undergoing chemotherapy, even after adjusting for potential confounding factors. Moreover, compared with patients with a baseline NLR \ 3.1 and decreased after chemotherapy, the HR for patients with a baseline NLR C 3.1 and elevated after chemotherapy was 2.47, indicating that an elevated baseline NLR with postchemotherapy NLR increase was the strongest prognostic factor for patients undergoing chemotherapy. These markers will help identify potential advanced pancreatic cancer candidates who will and will not benefit from chemotherapy. The postchemotherapy NLR change after two cycles of chemotherapy also had value in predicting prognosis. Nonetheless, given the dismal prognosis of patients with advanced pancreatic cancer, it may be better if we know the response to chemotherapy in a short time window (e.g., a cycle) so that we can make a timely change. The observation that the predicting value of the NLR variation in the control group was inferior to that of postchemotherapy change indicates the prognostic significance of the postchemotherapy NLR change for patients who underwent chemotherapy. NLR is an important and widely available marker of systematic inflammation and is related to various
biochemical and cellular activities.9–15 The importance of inflammatory response to pancreatic cancer has been well recognized in recent years.1–4 Inflammatory cells surrounding cancer cells have been confirmed to contribute an important role in pancreatic cancer initiation and prognosis.1–4 For example, Ino et al.22 systematically determined tumor-infiltrating immune/inflammatory cells in pancreatic cancer and analyzed their clinicopathological impact. They found that higher levels of neutrophils or the ratio of Tregs to CD4?T (%Treg) were significantly associated with poorer prognosis, whereas higher levels of tumor-infiltrating CD4?T or CD8?T were significantly associated with better prognosis.22 In another study, Fogar et al.23 confirmed that lower total lymphocyte counts in blood for patients with pancreatic cancer was an index of adverse prognosis. K-Ras activating mutations are the most common genetic alterations in pancreatic cancer1,4 and activation of K-Ras/RAF/ MEK signaling can stimulate neutrophils accumulation followed by intensive inflammatory reaction.24 The NLR offers important prognostic information for patients with operable and inoperable pancreatic cancer.10,11,14,16,25 For example, Garcea et al.11 identified 74 consecutive patients who underwent pancreaticoduodenectomy for pancreatic cancer and showed that a NLR [ 5 presented a disease-free survival of 12 months compared with
674
G. Luo et al.
TABLE 2 Univariate and multivariate analysis for overall survival of all patients using the Cox proportional hazards model including baseline NLR and postchemotherapy NLR change Characteristic
Parameter
No.
Univariate analysis
Multivariate analysis
HR
95 % CI
P
HR
95 % CI
P /
\60
174
1
/
/
1
/
C60
183
1.36
1.10–1.69
0.004
1.26
1.01–1.57
0.038
Gender
Male Female
223 134
1 0.79
/ 0.63–0.99
/ 0.035
1 0.84
/ 0.68–1.06
/ 0.137
Tumor size (cm)
\5
225
1
/
/
C5
132
1.01
0.81–1.26
0.940
Tumor location
Head
127
1
/
/
Others
230
1.16
0.93–1.45
0.179
Tumor spread
Locally
82
1
/
/
1
/
/
distant
275
1.61
1.24–2.08
0.000
1.53
1.18–1.99
0.002
CA19-9 (U/ml)
\300
120
1
/
/
1
/
/
C300
237
1.61
1.28–2.02
0.000
1.50
1.18–1.91
0.001
Albumin (g/dl)
\3.1
33
1
/
/
C3.1
324
Age
ECOG
NLR change
0.93
0.64–1.35
0.719
1
/
/
284
1.11
0.80–1.54
0.549
0
42
1 2
31
1.66
1.04–2.65
0.035
\3.1 ; \3.1 :
64 127
1 1.16
/ 0.85–1.57
/ 0.349
1 1.23
/ 0.90–1.67
/ 0.198
C3.1 ;
82
1.41
1.01–1.97
0.043
1.23
0.87–1.72
0.242
C3.1 :
84
2.47
1.77–3.45
0.000
2.39
1.71–3.34
0.000
Forty-six patients in the whole cohort had no neutrophil-to-lymphocyte ratio (NLR) information after chemotherapy
1.00
CA carbohydrate antigen, CI confidence interval, ECOG Eastern Cooperative Oncology Group performance status, HR hazard ratio, ; decreased, : increased, / no value
0.75
NLR < 3.1 ↓ HR = 1 NLR < 3.1 ↑ HR = 1.31, P = 0.141 NLR ≥ 3.1 ↓ HR = 1.49, P = 0.053
0.00
0.25
0.50
NLR ≥ 3.1 ↑ HR = 2.24, P = 0.000
0 No. at risk NLR < 3.1 ↓ NLR < 3.1 ↑ NLR ≥ 3.1 ↓ NLR ≥ 3.1 ↑
5
10
15
20
25
30
5 8 3 4
4 5 3 4
2 3 2 2
Time (month) 45 123 59 70
37 79 38 26
16 35 11 7
10 24 5 6
FIG. 2 Kaplan–Meier survival curves according to baseline neutrophil-to-lymphocyte ratio (NLR) and postchemotherapy NLR change after two cycles of chemotherapy. HR hazard ratio, No. number
52 months for those patients with NLR \ 5 (P \ 0.001). In another study, Sugiura et al.16 analyzed 83 patients with advanced pancreatic cancer and gastric outlet obstruction who underwent gastroenterostomy, and demonstrated that a
preoperative NLR C 4 was significant for independent prognostic factors. However, further evidence is needed to confirm the role of NLR in patients with advanced pancreatic cancer undergoing chemotherapy, which has clinical significance for more than 80 % of patients with pancreatic cancer who are not candidates for curative resection.6,7 NLR could predict the clinical outcomes in cancer patients treated with chemotherapy.17–20 For example, Yao et al.19 retrospectively reviewed 182 patients with advanced non-small cell lung cancer who were treated with first-line platinum-based chemotherapy and showed that a high pretreatment NLR (HR = 1.761; P = 0.020 for overall survival) was an independent prognostic factor. In another study, Lee et al.20 analyzed 174 patients with advanced gastric cancer who were treated with chemotherapy and found that NLR and changes of NLR after one cycle of chemotherapy are independent prognostic factors for overall survival. In this study, baseline NLR and postchemotherapy NLR change after one cycle of chemotherapy are independent prognostic factors for overall survival for advanced pancreatic cancer patients undergoing chemotherapy.
675
NLR < 3.1 NLR ≥ 3.1 HR = 1.72, P = 0.004
0.00
0.25
0.50
0.75
A
1.00
NLR and Pancreatic Cancer Patients Underwent Chemotherapy
0
5
10
48 77
19 20
1.00
NLR < 3.1 NLR < 3.1
20
25
30
8 6
4 5
2 2
2 1
2 1
NLR < 3.1 ↓ HR = 1 NLR < 3.1 ↑ HR = 1.99, P = 0.976
0.75
B
15
Time (month)
No. at risk
0.00
0.25
0.50
NLR ≥ 3.1 ↓ HR = 1.80, P = 0.675 NLR ≥ 3.1 ↑ HR = 1.89, P = 0.191
0
5
10
NLR < 3.1 ↓ NLR < 3.1 ↑ NLR ≥ 3.1 ↓ NLR ≥ 3.1 ↑
15
20
25
30
0 0 2 0
0 0 2 0
0 0 2 0
Time (month)
No. at risk 5 29 16 31
2 9 7 5
0 4 4 1
0 1 3 1
FIG. 3 a Kaplan–Meier survival curves according to baseline neutrophil-to-lymphocyte ratio (NLR). b Kaplan–Meier survival curves according to NLR change compared to baseline and after 1 month. HR hazard ratio, No. number
In this study, both baseline NLR and postchemotherapy NLR changes were found to be related to tumor spread and serum CA19-9 levels. High serum CA19-9 levels and tumor spread were demonstrated to be associated with a poor prognosis and serum CA19-9 levels correlated with tumor burden and stage.24–27 The previous study has showed that higher tumor stage was associated with elevated NLR in non-small cell lung cancer (P = 0.019), which was confirmed in the current study.28 Although a higher NLR was associated with an advanced stage and serum CA19-9 levels, NLR remained an independent predictor of prognosis in the adjusted models by multivariate analysis. Therefore, the association between higher NLR and prognosis was not solely explained by the advanced stage of cancer.28 As mentioned above, the NLR is a ratio and it may change if either the number of neutrophils or lymphocytes changes. Several well-known factors including chemotherapy toxicity, chronic inflammatory diseases, granulocyte colony-stimulating factor administration, pathogenic inflammation,29 and
other diseases30,31 could induce the number of neutrophils and/or lymphocytes changes, which may complicate the use of NLR. Therefore, we need to keep these conditions in mind in clinical practice. The major limitation of the study is the retrospective finding on the basis of a single institution. Nonetheless, this is the first study showing that NLR is an independent indicator of prognosis for patients with pancreatic cancer undergoing chemotherapy. In addition, this is a relatively large-sized sample for this study compared with other related studies. Moreover, we not only determined the role of prechemotherapy NLR, but also NLR change after one cycle of chemotherapy to the prognosis of patients with advanced pancreatic cancer. Nonetheless, NLR is affected by internal and external factors, including acute and chronic infection and lifestyle-related habits.32 Further multicentric prospective studies are needed to optimize NLR cut-off level and determine its strength and shortages. In conclusion, both baseline NLR and postchemotherapy NLR changes are identified as independent prognostic predictors for patients with advanced pancreatic cancer undergoing chemotherapy. These factors could be used to predict therapeutic response to chemotherapy for these patients. ACKNOWLEDGMENT This study was supported in part by the Sino-German Center (GZ857), by the Science Foundation of Shanghai (13ZR1407500), by the Shanghai Rising Star Program (12QH1400600, 14QA1400900), by the Fudan University Young Investigator-promoting program (20520133403), and by the National Science Foundation of China (Grant No. 81101807, No. 81001058, No. 81372649, No. 81372653, and No. 81172276). DISCLOSURE The authors declare no potential conflicts of interest in this study.
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