Abstract
Background/Aim: Surgery is an important pancreatic ductal adenocarcinoma (PDAC) treatment; existing markers are inadequate prognostic indexes. We herein evaluated the utility of the FA score (fibrinogen/albumin ratio) for predicting PDAC postoperative outcomes. Patients and Methods: We analysed the data of 67 PDAC patients who underwent surgical resection. The relationship between postoperative outcomes and the FA score was investigated. Performance of the FA score was compared to that of other variables and prognostic indexes. Results: No patient with FA ≥130 survived >3 years, whereas all patients who survived longer had FA <130. The FA score was superior to all other indexes for predicting postoperative outcomes. Patients with FA ≥130 vs. <130 had significantly shorter overall and recurrence-free survival. Conclusion: The FA score is useful for predicting PDAC postoperative outcomes. Preoperatively, it may detect patients likely to have poor postoperative prognoses who may benefit from adjuvant or neoadjuvant therapy, thus improving outcomes.
Surgery is a potentially curative treatment for pancreatic ductal adenocarcinoma (PDAC) (1). Recently, the effectiveness of a multimodal approach that combines surgical resection with both adjuvant and neoadjuvant therapies has been reported in terms of survival (2). However, PDAC has a poorer prognosis than other cancers, although long-term survival has improved slightly (3). Furthermore, postoperative recurrences occur, even in the early stages. It is difficult to accurately evaluate the prognosis of PDAC based on the existing markers or indexes.
A better system is needed to evaluate prognosis before PDAC surgery to help detect high-risk patients and improve the indications for adjuvant and neoadjuvant therapy. Several prognostic factors utilizing systemic inflammation-based scores associated with cancer have been explored. According to previous reports, the C-reactive protein (CRP)/albumin ratio (CAR) (4), Glasgow Prognostic Score (GPS) (5), neutrophil/lymphocyte ratio (6), platelet/lymphocyte ratio (PLR) (7), and Prognostic Nutritional Index (PNI) have value as prognostic markers in PDAC or pancreatic cancer.
An additional index, the FA score, is the proportion of preoperative plasma fibrinogen to albumin. When a cancer progresses, the inflammatory response against it strengthens, resulting in an increase in fibrinogen and a decrease in albumin. Fibrinogen serves as a scaffold that binds growth factors, which in turn promote cellular responses associated with tumour cell adhesion, proliferation, and migration during cell growth and angiogenesis (8). Guo et al. (9) reported that fibrinogen levels were significantly higher in pancreatic cancer than in benign pancreatic tumours; moreover, elevated fibrinogen levels had a positive relationship with tumour stage and might be predictive of distant metastasis. Regarding albumin levels, malnutrition is common in patients with cancer, and serum albumin is a common indicator of nutritional status and a predictor of cancer survival (10). Thus, the FA score reflects the cancer severity. The FA score is a simple prognostic tool that has been studied in various malignant diseases of the lung, breast, oesophagus, gastric regions, liver, gallbladder, colorectal regions (including liver metastasis), and ovaries, as well as in sarcoma, leukaemia, and glioma. However, the role of the FA score as a prognostic marker in PDAC has not been previously investigated. In this study, we evaluated the utility of the preoperative FA score for predicting outcomes after surgical resection in patients with PDAC.
Patients and Methods
Ethics approval and informed consent. The procedures followed were in accordance with the ethical standards of the Institutional Review Board of Tokyo Medical University Hachioji Medical Center (T2020-0049) and with the Helsinki Declaration of 1975, as revised in 1983. Informed consent was obtained from all patients.
Patients. We retrospectively analysed clinical data of 111 patients who underwent surgical resection and had a postoperative histopathological diagnosis of PDAC at the Tokyo Medical University Hachioji Medical Center between July 2007 and May 2020. Patients with a histological diagnosis other than adenocarcinoma, including intraductal papillary mucinous carcinoma, neuroendocrine carcinoma, or benign tumour, were excluded. Patients with unresectable PDAC as per National Comprehensive Cancer Network (NCCN) guidelines (11) (distant metastasis or locally advanced tumour) were also excluded; only patients with resectable or borderline resectable PDA were included in our analysis. Additionally, we excluded patients who underwent neoadjuvant therapy (n=11) and those without preoperative fibrinogen or albumin assessments (n=33). We excluded neoadjuvant therapy patients because the proper evaluation timing of the FA score is unclear in these patients. After applying these criteria, 67 patients were eligible for inclusion.
Preoperative evaluation. A preoperative blood test was performed as close as possible to the time of surgery. All patients with obstructive jaundice and signs of cholangitis underwent biliary decompression before surgery. Endoscopic retrograde cholangiopancreatography was most often performed for bile reduction, and an endoscopic retrograde biliary drainage tube, metallic stent, or endoscopic naso-biliary drainage tube was inserted. No patients had signs of cholangitis at the time of surgery. Multiple prognostic indexes including the CAR (4), FA score, GPS (5), PLR (7), and PNI (12) were calculated based on blood tests. The FA score was calculated as follows: fibrinogen (mg/dl)/albumin (g/dl).
Surgical information. The resectability status (resectable and borderline resectable) was defined based on the NCCN guidelines (11). “Resectable” was defined as having no arterial superior mesenteric vein or portal vein contact, or as ≤180° contact without vein contour irregularity. “Borderline resectable” was defined as having more contact than a resectable tumour, but less than an unresectable tumour.
Pathological diagnosis. The pathological diagnosis was based on the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) guidelines (13), which include the tumour, nodes, and metastasis (TNM) classification, stage, and differentiation. Additionally, the microscopic lymphatic and venous invasion around the main tumour was evaluated in accordance with the AJCC/UICC guidelines. Microscopic histopathology including immunostaining (mainly D2-40 for lymphatic invasion and Elastica van Gieson for venous invasion) was used for diagnosis.
Postoperative course. The postoperative pancreatic fistula was graded according to the International Study Group on Pancreatic Fistula definition (14) as follows: grade A, transient fistula with no clinical impact; grade B, fistula requiring a change in management or an adjustment in the clinical pathway; grade C, fistula requiring a major change in clinical management or a deviation from the normal clinical pathway.
FA score evaluation. An FA score cut-off value was determined using a scatter plot of FA scores and postoperative survival. Two patient groups were defined based on whether the FA score was above or below the cut-off value, and patient characteristics were compared between the groups. The risk factors affecting overall survival (OS) and recurrence-free survival (RFS) were evaluated using multivariate analyses.
Statistical analysis. Continuous variables are expressed as the median and range (minimum to maximum); the Mann-Whitney U-test was used for comparisons between groups. Categorical variables are expressed as a count (%); they were compared using the chi-square test or Fisher’s exact test, as required. Univariate and multivariate analyses were performed using Cox proportional hazards regression analyses with forward-selection of the likelihood ratio. The prognosis was evaluated using the Kaplan-Meier method, and the statistical difference was evaluated using the log-rank test. Statistical tests were two-tailed, and significance was set at p<0.05. All statistical analyses were performed using IBM SPSS Statistics, version 26.0 (IBM Corp., Armonk, NY, USA).
Results
Patient characteristics. Patient characteristics and comparisons between the FA score groups are shown in Table I. The FA score cut-off value was defined as 130, as described below. Fibrinogen levels were significantly higher and albumin levels were significantly lower in the FA ≥130 group than in the FA <130 group. The white blood cell count and CRP levels were also significantly higher in the FA ≥130 group. Tumour marker levels were not significantly different between groups. Finally, all prognostic scores (CAR, FA score, GPS, PLR, and PNI) were significantly worse in the FA ≥130 group. In terms of pathological diagnosis, the most common AJCC/UICC stage was IIB, [38 patients (56.7%)]. No cases of stage IV disease were observed, because unresectable cases were excluded, and no patient had distant metastasis. Regarding prognosis, the median OS was 22.9 months and the median RFS was 11.7 months. No patient died due to surgery.
FA score cut-off calculation. The correlation between FA scores and postoperative survival is shown in Figure 1. Notably, no patient with an FA score ≥130 survived longer than 3 years, whereas all patients who survived beyond this time point had an FA score <130. Thus, the FA score cut-off value was defined as 130.
Risk factors for OS. Risk factors for OS were evaluated by univariate and multivariate analyses (Table II). Age, albumin, carcinoembryonic antigen (CEA), CA19-9 levels, FA scores, FA score ≥130, PNI, resection margin, AJCC/UICC stage, and venous invasion were found to be directly associated with reduced survival. In the multivariate analysis, CEA level, FA score ≥130, and venous invasion were identified as independent risk factors for reduced survival.
Comparison of OS. Figure 2a shows the comparison of OS between the FA <130 and ≥130 groups. Patients with an FA score ≥130 had a significantly shorter OS than those with an FA score <130 (p=0.005).
Comparison of RFS. Figure 2b shows the comparison of RFS between the FA <130 and ≥130 groups. The FA ≥130 group had a significantly shorter RFS than did the FA <130 group (p=0.015).
Discussion
The present study showed that the FA score is a good prognostic marker in patients with PDAC. An FA score ≥130 was an independent risk factor for postoperative OS and RFS, and patients with an FA score <130 had a significantly better prognosis than those with an FA score ≥130. The FA score can be a useful prognostic marker before surgery of PDAC. This score can help the preoperative detection of patients with poor prognosis who may benefit from adjuvant or neoadjuvant therapy.
The scatter plot showed that patients with a high FA score had a poor prognosis, whereas patients with a low FA score had a survival time varying from <1 year to >6 years. This suggests that a high presurgical FA score can help detect patients with reduced chances of postsurgical survival.
Although the GPS and PNI were also linked to survival in the univariate analysis, only the FA score remained significantly associated with survival in the multivariate analysis. The GPS is already known as a good prognostic marker for PDAC (15); a modified GPS, which has a minor change in CRP and albumin score with respect to the original GPS, has been described in the AJCC/UICC classification. However, our results suggested that the FA score performed better than did the GPS for predicting postoperative outcome in patients with PDAC.
Apart from preoperative blood tests, prognosis in pancreatic cancer depends on various factors like tumour size, histologic grade, vascular invasion, lymph node metastasis, and intrapancreatic perineural invasion. Herein, venous invasion was an independent risk factor for reduced survival, which is consistent with the findings of a previous report (16).
The present study had several limitations. First, it was performed in a single centre with a relatively small number of patients. Second, we did not evaluate changes in the FA ratio in relation to neoadjuvant therapy. Previous reports have suggested that variations in other parameters like the CA19-9 level and neutrophil/lymphocyte ratio after neoadjuvant therapy are associated with prognosis (6). Third, due to its retrospective nature, this study could not assess the role of the FA score in the decision-making process. A large, prospective, multicentre study including a more heterogeneous population is necessary to confirm the utility of this score for PDAC prognosis prediction when applying the proposed cut-off value.
Conclusion
Our findings suggest that the FA score can be a useful prognostic tool before surgical resection of PDAC. Although further studies will be needed, this score may help in the preoperative detection of patients likely to have a poor postoperative prognosis and may thus benefit from adjuvant or neoadjuvant therapy.
Footnotes
Authors’ Contributions
K.T. developed the study concept and design, participated in the statistical analysis and data interpretation, and drafted the manuscript. All Authors contributed to data acquisition, critical manuscript revision, and final manuscript approval.
Conflicts of Interest
The Authors declare no conflicts of interest in regard to this study.
- Received October 6, 2020.
- Revision received October 19, 2020.
- Accepted October 22, 2020.
- Copyright © 2020 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.