Prognostic impact of preoperative NLR and CA19-9 in pancreatic cancer

Pancreatology xxx (2015) 1e7

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Original article

Prognostic impact of preoperative NLR and CA19-9 in pancreatic cancer Tadafumi Asaoka a, b, *, Atsushi Miyamoto a, Sakae Maeda a, Masanori Tsujie a, Naoki Hama a, Kazuyoshi Yamamoto a, Masakazu Miyake a, Naotsugu Haraguchi a, Kazuhiro Nishikawa a, Motohiro Hirao a, Masataka Ikeda a, Mitsugu Sekimoto a, Shoji Nakamori a a b

Department of Surgery, National Hospital Organization, Osaka National Hospital, Osaka, Japan Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Available online xxx

Background: Recently, several preoperative proinflammatory markers and nutritional factors such as neutrophil-to-lymphocyte ratio (NLR) and prognostic nutrition index (PNI) have been reported as significant predictor for poor prognosis of various malignant tumors. In this study, we evaluated the prognostic values of these preoperative parameters in patients with resectable pancreatic head cancer. Methods: We retrospectively reviewed consecutive patients who underwent PD for pancreatic head cancer between 2007 and 2012. A total of 46 patients were enrolled in this analysis. Preoperative parameters such as CRP, CA19-9, NLR and PNI at the time of presentation were recorded as well as overall survival. Cancer specific survival was assessed using KaplaneMeier method. Univariate and multivariate Cox regression models were applied to evaluate the prognostic relevance of preoperative parameters. The correlations between CA19-9 values, NLR and pathological findings, first recurrence site were respectively reviewed. Results: In multivariable analysis preoperative high NLR (S2.7) and high CA19-9 (S230) were independent prognostic factors for poor survival (P value: 0.03 and 0.025, respectively). KaplaneMeier survival analysis demonstrated the overall 2-year survival rate in patients with high NLR or high CA19-9 were 37.5% compared with 89.9% in patients with low NLR and low CA19-9. Conclusion: Preoperative NLR and serum CA19-9 offer significant prognostic information associated with overall survival following PD in the patients with pancreatic head cancer. Copyright © 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

Keywords: Pancreatic head cancer Pancreatoduodenectomy CA19-9 Neutrophil-to-lymphocyte ratio (NLR) Pancreatic cancer Neoadjuvant chemotherapy

Introduction Currently, pancreatic cancer is one of the most leading causes of cancer death with a poor prognosis, because of its high malignant potential and the difficulty to detect at an early stage [1]. Surgical

Abbreviations: CA19-9, Carbohydrate antigen 19-9; NLR, Neutrophil-tolymphocyte ratio; PLR, Platelet-to-lymphocyte ratio; PNI, Onodera's prognostic nutrition index, PNI ¼ (10  Alb) þ (0.005  Total Lymphocyte Count); PD, Pancreatoduodenectomy. * Corresponding author. Department of Surgery, National Hospital Organization, Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka, 540-0006, Japan. Tel.: þ81 6 6942 1331; fax: þ81 6 6946 5660. E-mail address: [email protected] (T. Asaoka).

treatment of pancreatic cancer includes multiple modalities, but surgical resection is the only curative option for pancreatic cancer. However, the prognosis of patients who undergo pancreatectomy is generally poor due to the high recurrence rate. Under standard treatments, the 5-year survival rates are 20%e24% and still unsatisfied [2e4]. Recently, neoadjuvant chemotherapy has been a major research focus to improve the outcome for pancreatic cancer [5,6]. Neoadjuvant chemotherapy has the advantages not only to perform the early treatment of micrometastases but also to delay surgery and spare those who already have occult metastases [7e10]. Actually, it has been reported that patients presenting with locally advanced and unresectable tumors should be offered neoadjuvant therapy and then re-evaluated for resection. It suggests that the advantages

http://dx.doi.org/10.1016/j.pan.2015.10.006 1424-3903/Copyright © 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

Please cite this article in press as: Asaoka T, et al., Prognostic impact of preoperative NLR and CA19-9 in pancreatic cancer, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.10.006

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of preoperative therapy include the downstaging of disease to achieve curative resection. However, those advantages are still controversial for resectable pancreatic cancer, because it may also have disadvantages such as delaying surgical resection. In the patients without sufficient effect of preoperative therapy, it can be a waste of time and may result in the patients missing the chance for surgery. In this point, the identification of novel preoperative prognostic marker might be useful to stratify the treatment options such as neoadjuvant therapy and surgery or chemotherapy after surgery. The prediction of tumor progression or recurrence after curative resection is limited to the use of histopathological features such as tumor size, differentiation, lymph node metastasis and resection margin. However, several preoperative inflammatory markers and nutritional factors such as neutrophil-to-lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and Onodera's prognostic nutrition index (PNI) recently have been reported as significant predictor for patients' survival in various malignant tumors [11e19]. These findings warrant further comparison of these parameters with other known prognostic markers such as C-reactive protein and CA19-9 and its possible use in predicting surgical outcome. The purpose of this study was to evaluate the predictive values of preoperative CRP, CA19-9, NLR, PLR and PNI in patients undergoing curative resection for pancreatic head cancer. Materials and methods We retrospectively reviewed consecutive 68 patients who underwent PD for invasive ductal adenocarcinoma in pancreatic head at Osaka National Hospital between April 2007 and December 2012. Out of them, 22 cases with synchronous distant metastasis such as paraaortic lymph node metastasis or liver metastasis were eliminated from this study to prevent the influence of distant metastasis. In total, 46 cases who underwent macroscopically curative resection were enrolled in this study. Preoperative clinical findings including age, gender, coexistence of diabetes mellitus, incidence of jaundice and serum parameters such as hemoglobin, albumin, CEA, CA19-9 values and inflammatory and nutritional markers such as NLR, PLR and PNI were analyzed. The measurement of serum parameters was performed within 1 month before the operation. We used the data after biliary drainage in the patients with jaundice. All patients underwent subtotal-stomach preserving PD, and reconstruction for PD was performed according to modified Child method. Surgery If patients had the distant metastasis, tumor infiltration into the hepatic artery or superior mesenteric artery, or the occlusion of the portal or superior mesenteric vein with cavernous transformation due to tumor invasion, they were included into the unresectable cases. In the cases where the pancreatic tumor was fixed with the PV or SMV, it was resected together with the pancreas. All patients underwent D2 lymph node dissection. Reconstruction after PD was performed according to modified Child method. Postoperative course If the patient's performance status was adequate, postoperative follow-up consisted of a routine physical examination and laboratory test, including the serum level of CEA and CA19-9. Both chest X-ray and abdominal CT were performed every 3 months for the first 3 years, and the presence or absence of cancer recurrence was carefully confirmed. If patients had no sign of recurrence, they were

followed up at 6 month intervals. Among 46 patients, 26 patients received adjuvant chemotherapy using Gemcitabine or S-1. Adjuvant chemotherapy has become a standard treatment in our institute since 2007 after the CONKO-001 study were published. Statistical analysis Continuous variables were expressed as mean values and standard deviations. Univariate and multivariate Cox regression models were applied to evaluate the prognostic relevance of preoperative parameters. The variables with P < 0.05 in univariable analysis were included as co-variables in the final model. Cancer specific survival probabilities were assessed with using KaplaneMeier method from the time of surgery to the time of death or last follow-up, which was updated at September 2013. The correlations between CA19-9 values, NLR and pathological findings, first recurrence site were respectively reviewed. Results In our institution, 46 patients were comprised of 24 females and 22 males with a mean age of 67 years. There were no postoperative deaths at 90 days and the median overall survival of all 46 patients was 26.3 months and median disease free survival was 9.6 months. The overall 1-, 3-, and 5-year survival rates were 77.3%, 35.3% and 35.3%. In total, 16 out of 46 patients (35.3%) have survived for more than 36 months after surgery. The mean values of all serum parameters and the results of Cox regression hazard models for predictors of overall survival are shown in Table 1. We used mean value as the cutoff point of each parameter. Univariate analysis identified 6 preoperative parameters and 2 histological findings as prognostic factors for poorer outcome, including gender (male), low lymphocyte counts (<1700) high platelet counts (S23.5), high CA19-9 values (S230), high NLR (S2.7), low PNI (<47) and the presence of anterior serosal or retroperitoneal invasion. After multivariate analysis, a total of three factors remained independent predictors for overall survival. Especially, high CA19-9 values (S230) and high NLR (S2.7) had significant influence on the poor survival (Table 1). KaplaneMeier survival analysis of patients with high CA19-9 values (S230) revealed a significantly poor overall survival compared to the patients with low CA19-9 values (<230) (Fig. 1). The 1-,2- and 5-year overall survival rates were 80.6% 66.3%, 53.1% in the patients with CA19-9 values < 230 U/ml (n ¼ 32) and 69.2%, 23.1%, 0% in the patients with CA19-9 values S230 U/ml (n ¼ 14), respectively (p ¼ 0.0003). Fig. 2 shows the overall survival according to the NLR. The patients with NLR <2.7 had significantly better survival than patients with NLR S2.7. The overall 1-, 2- and 5-year survival rates were 84.0%, 76.0% and 51.5% in patients with NLR <2.7 and 68.6%, 21.1%, 0% in patients with NLR S2.7, respectively. Our analysis showed that patient's survival after PD can be predicted using the combination of these parameters. If one of these parameters were elevated more than our cutoff values, their overall and disease free survivals were significantly poorer than those in patients with low CA19-9 (<230) and NLR (<2.7) (2-year OS, 37.5% vs 88.9%, p ¼ 0.0004, 1-year DFS, 18.2% vs 88.9%, p ¼ 0.001, respectively) (Fig. 3a, b). The pathological findings according to preoperative CA19-9 values and NLR are shown in Table 2. The incidences of large tumor spread and retroperitoneal invasion were more frequently observed in the patients with high CA19-9 values (S230) and high NLR (S2.7), respectively. Fig. 4 presents the pattern of first recurrence site and the time to the recurrence from the operation. Early recurrences were

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Table 1 Univariate and multivariate (Cox regression) survival analysis. Preoperative Factors

Mean ± SD

Category

Number

Univariate

Hazard ratio

p value Age

67 ± 8.9

Gender Female/Male Diabetes mellitus Jaundice BMI

23 ± 3.1

Serum parameter WBC (counts/ml)

5820 ± 1529

Neu (counts/ml)

3857 ± 1087

Lym (counts/ml)

1607 ± 609

Hemoglobin (g/dl)

12.0 ± 1.5

Platelet (  104/ml)

23.5 ± 6.2

CRP (mg/l)

1.0 ± 1.2

Albumin (g/dl)

4.0 ± 0.5

T-Bil (mg/dl)

1.6 ± 1.5

CEA (ng/ml)

4.0 ± 4.2

CA19-9 (U/ml)

232 ± 272

NLR

2.7 ± 1.2

PNI

47 ± 6.8

Plt/Lym

163 ± 70

Radiologic findings TNM classification T N M Histological findings Tumor size (mm) Grade

Lymph node status Anterior serosal invasion Retroperitoneal invasion Portal invasion Resection margin

<67 S67 Male Female e þ e þ <23 S23

11 35 22 24 36 10 23 23 27 19

<5820 S5820 <3900 S3900 <1700 S1700 <12 S12 <23.5 S23.5 <1.0 S1.0 <4.0 S4.0 <1.6 S1.6 <4.0 S4 <230 S230 <2.7 S2.7 <47 S47 <163 S163

25 21 25 21 27 19 24 22 24 22 37 9 24 22 31 15 35 11 32 14 26 20 21 25 27 19

&T2 ST3 N0 N1 M0 M1

8 38 13 33 46 0

0.218

<30 S30 Well moderate Poor other þ e þ e þ e þ e R0 R1

20 26 10 34 1 1 29 17 21 25 20 26 14 32 37 9

0.143

identified in patients with high CA19-9 values and high NLR. The liver metastasis was the most frequent recurrence site and predominantly observed in patients with early recurrence. Discussion In our study, we evaluated the preoperative parameters to predict subsequent prognosis after PD for pancreatic head cancer

Multivariate

p value

95% CI

0.970 0.024

2.98

1.08e8.78

0.034

0.760 0.347 0.788

0.884 0.956 0.039

not applicable

0.985 0.019

2.06

0.83e5.55

0.119

0.0008

3.707

1.26e11.45

0.018

0.0048

3.668

1.45e9.81

0.006

0.0034

1.216

0.42e3.75

0.724

0.016

1.563

0.57e4.46

0.389

0.024

2.7

0.83e9.09

0.098

0.810 0.072 0.265 0.927

0.833

0.544 not available

0.280

0.333

0.574 0.304

and demonstrated that elevated CA19-9 values and NLR can be reliable predictive markers for poor prognosis. We found that the baseline CA19-9 and NLR (mean value) in our institute were independent prognostic factor for OS (CA19-9 < 230, HR 0.345; 95% CI: 0.136e0.879, P ¼ 0.0257, NLR < 2.7, HR 0.373; CI: 0.153e0.910, P ¼ 0.0303). Furthermore, the advanced findings in pathology and early recurrent cases were more frequently observed in cases with high CA19-9 values (S230). The preoperative CA19-9 levels were

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Fig. 1. Overall and disease free survival according to CA19-9 values. The overall and disease free survival of patients with CA19-9 < 230 U/ml was significantly better than that of patients with CA19-9 S 230 U/ml.

Fig. 2. Overall and Disease free survival according to NLR. The overall and disease free survival of patients with NLR < 2.7 was significantly better than that of patients with NLR S 2.7.

Fig. 3. Overall and disease free survival according to the combination of CA19-9 values and NLR. KaplaneMeier survival analysis demonstrated the overall 2-year survival rate in patients with CA19-9 S 230 U/ml or NLR S 2.7 were 37.5% compared with 88.9% in patients with CA19-9 < 230 and NLR < 2.7 (p ¼ 0.0004) (Fig. 3a). The disease free survival of patients with CA19-9 < 232 U/ml and NLR < 2.7 was significantly better than that of patients with CA19-9 S 230 U/ml or NLR S 2.7 (p ¼ 0.0001) (Fig. 3b).

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Table 2 Distribution of pathological findings stratified by CA19-9 and NLR. Category Tumor size(mm) Nodal status Anterior serosal invasion Retroperitoneal invasion Portal vein invasion Resection margin Cytology Adjuvant chemotherapy

<30 mm S30 mm Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive No Yes

CA19-9 < 230 (U/ml)

CA19-9 S 230 (U/ml)

p value

NLR < 2.7

NLR S 2.7

p value

17 15 13 19 20 12 19 13 23 9 26 6 31 1 13 19

3 11 4 10 5 9 7 7 9 5 11 3 13 1 7 7

0.046

14 12 12 14 15 11 18 8 19 7 21 5 26 0 11 15

6 14 5 15 10 10 8 12 13 7 16 4 18 2 9 11

0.106

Fig. 4. Time to the first recurrence from the operation. Early recurrences were identified in patients with high CA19-9 values and high NLR. Liver metastasis was predominantly observed in patients with early recurrence within 6 months.

significantly correlated with tumor size, and early recurrences also were detected in cases with high CA19-9 values. These findings support the notion that preoperative CA19-9 values could reflect the biological aggressiveness and the presence of distant micrometastases. The CA19-9 directly reflects the tumor malignant potential and it has been reported as a predictive marker of tumor staging and resectability and furthermore, several reports have suggested that the serial measurement of CA19-9 can predict the response to chemotherapy. However, the optimal cutoff values have remained controversial [20e22]. We persisted in the preoperative CA19-9 values, because it could be made possible to stratify the treatment option such as neoadjuvant therapy and surgery. We made focus on the only resectable cases who underwent PD for pancreatic head cancer to eliminate the heterogeneity of tumor localization and treatment, because the PD is more invasive surgical procedure than the distal pancreatomy. Actually, it has been reported that the mortality rate in PD is about 5% and higher than in distal pancreatomy. One of our limitations, the TNM classification was not related to survival. In most of the cases (n ¼ 38, 82.6%), T stages were more than T3 tumors. We think it is because of small sample size and sample imbalance.

0.435 0.093 0.555 0.607 0.833 0.538 0.555

0.141 0.604 0.047 0.555 0.948 0.0992 0.855

Another limitation in the interpretation of CA19-9 levels for prognostic purposes is that CA19-9 levels are affected by concurrent jaundice. It has been well known that acute cholangitis present extremely elevated serum CA19-9 [23]. Therefore, we used the data after biliary drainage to avoid any bias in the patients with jaundice.However, it is still a small cohort of 46 patients, further studies would be validated these results. One more limitation of the clinical utility of CA19-9 antigen is that it is limited by the corresponding Le antigen phenotype. It has been reported that CA19-9 antigen cannot be used as a biomarker in patients with Lea-b- phenotype. Approximately 5% of the population are believed to lack the Lewis antigen glycosyltransferase enzyme required to synthesize CA19-9 [24]. Actually, we could not detect any elevations of serum CA19-9 of 3 patients in our study (6.5%), although they had the recurrence during postoperative course. In those cases, the patients with NLR 1.7 and 2.1 survived more than 50.3 and 70.1 months, respectively, but the overall survival of the patient with NLR 3.8 was 9.0 months. Therefore, in the cases with Lea-b- phenotype, combination monitoring with NLR may be useful to predict the survival after PD. NLR and its role of prognostic biomarkers have been intensively explored and the correlation between high NLR and poor clinical outcome was assessed in different tumor including lung, colorectal, stomach, liver, and breast cancer [25e29]. The relationship between systemic inflammation and cancer progression has been supported and NLR is getting more attractive, because NLR is readily measurable in peripheral blood and directly reflects the systemic host inflammatory response. The clear evidence has been obtained that inflammation plays a critical role in tumor development, such as invasion and metastasis. Inflammation also affects the response to cancer treatment. It has been known that cancer cells produce myeloid growth factors which increased production of neutrophils. Cancer neutrophilia has been associated with poor survival in patients with metastatic melanoma and lung cancer [30,31]. On the other hand, cancer cells has been reported to decrease in lymphocyte function by producing immunologic cytokines, such as IL-10 and transforming growth factor beta [32]. When compared with other gastrointestinal tumors, adenocarcinoma of pancreas is thought to be associated with the most significant lymphocytopenia [33]. NLR may represent the two opposing inflammatory and immune pathways that exist together in cancer patients. NLR was reported to correlate with reduced survival in pancreatic cancer. For example, in the large cohort study of 474 pancreatic cancer including resectable and unresectable cases, high NLR (S2.3) was an independent poor prognostic factor. However,

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they mentioned multivariate Cox analysis was performed after ROC curved and there was a high risk of over fitting of data [34]. In the other cohort study, high NLR (>5) reported to be associated with reduced disease free survival following curative resection of pancreatic cancer [35]. Several studies have been reported the utility of NLR to predict the outcome in pancreatic cancer, however, there is still considerable variation about which cutoff value of NLR can be used to stratify the treatment option [35e41]. In our study, we determined a cut-off value of mean value 2.7 for the specific cohort of PC patients. We found a statistically significant association between NLR S 2.7 and poor clinical outcome in multivariate analysis, highlighting the independent value of this parameter. However, there are some limitations to be taken into account in our study. This is a retrospective data collection with no prospective study design. The cutoff values of preoperative serum CA19-9 and NLR should be validated in a prospective manner. A further implication is that the stratification of patients according to these markers should be confirmed in Neoadjuvant trials. In conclusion, preoperative NLR and serum CA19-9 offer significant prognostic information associated with overall survival following PD in the patients with pancreatic head cancer. Further independent prospective trials should be requested to confirm these results. Author roles Tadafumi Asaoka, performed research and participated in the study design, writing the paper, and data analysis. Atsushi Miyamoto, Sakae Maeda,Masanori Tsujie and Naoki Hama participated in obtaining clinical data. Kazuyoshi Yamamoto, Masakazu Miyake, Naotsugu Haraguchi, Kazuhiro Nishikawa, Motohiro Hirao, Masataka Ikeda and Mitsugu Sekimoto participated in the study design and suggestions. Shoji Nakamori participated in the study design, revising the paper, clinical diagnosis and data analysis. References [1] Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55(2):74e108. [2] Kuhlmann KF, de Castro SM, Wesseling JG, ten Kate FJ, Offerhaus GJ, Busch OR, et al. Surgical treatment of pancreatic adenocarcinoma; actual survival and prognostic factors in 343 patients. Eur J Cancer 2004;40(4):549e58. [3] Moon HJ, An JY, Heo JS, Choi SH, Joh JW, Kim YI. Predicting survival after surgical resection for pancreatic ductal adenocarcinoma. Pancreas 2006;32(1): 37e43. [4] Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H, Buchler MW. Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg 2004;91(5):586e94. [5] Eguchi H, Nagano H, Kobayashi S, Kawamoto K, Wada H, Hama N, et al. A phase I trial of combination therapy using gemcitabine and S-1 concurrent with full-dose radiation for resectable pancreatic cancer. Cancer Chemother Pharmacol; 73(2):309e315. [6] Tajima H, Ohta T, Kitagawa H, Okamoto K, Sakai S, Makino I, et al. Pilot study of neoadjuvant chemotherapy with gemcitabine and oral S-1 for resectable pancreatic cancer. Exp Ther Med; 3(5):787e792. [7] Ohigashi H, Ishikawa O, Eguchi H, Takahashi H, Gotoh K, Yamada T, et al. Feasibility and efficacy of combination therapy with preoperative full-dose gemcitabine, concurrent three-dimensional conformal radiation, surgery, and postoperative liver perfusion chemotherapy for T3-pancreatic cancer. Ann Surg 2009;250(1):88e95. [8] Palmer DH, Stocken DD, Hewitt H, Markham CE, Hassan AB, Johnson PJ, et al. A randomized phase 2 trial of neoadjuvant chemotherapy in resectable pancreatic cancer: gemcitabine alone versus gemcitabine combined with cisplatin. Ann Surg Oncol 2007;14(7):2088e96. [9] Evans DB, Varadhachary GR, Crane CH, Sun CC, Lee JE, Pisters PW, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol 2008;26(21):3496e502. [10] Varadhachary GR, Wolff RA, Crane CH, Sun CC, Lee JE, Pisters PW, et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol 2008;26(21):3487e95.

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Please cite this article in press as: Asaoka T, et al., Prognostic impact of preoperative NLR and CA19-9 in pancreatic cancer, Pancreatology (2015), http://dx.doi.org/10.1016/j.pan.2015.10.006