ABSTRACT
Background
This study aimed to examine whether preoperative serum total iron‐binding capacity (TIBC), which is directly proportional to transferrin level, correlates with long‐term outcomes after pancreatectomy.
Methods
Preoperative TIBC levels, calculated by summing serum iron and unsaturated iron binding capacity, were evaluated in 158 patients who underwent pancreatectomy for pancreatic cancer. We defined TIBC < 258 μg/dL calculated by receiver‐operating characteristic (ROC) analysis as low TIBC. We evaluated the relationship between preoperative TIBC levels and long‐term outcomes after pancreatectomy.
Results
Low preoperative TIBC levels were correlated with lower body mass index, higher rate of preoperative chemotherapy, lower albumin, and higher amount of intraoperative blood loss compared to those in high TIBC levels (p = 0.041, 0.046, 0.0002, 0.0032, respectively). Patients with low preoperative TIBC levels had significantly poorer overall survival (OS) and recurrence‐free survival (RFS) compared to that in high TIBC level in Kaplan–Meier analysis (p < 0.0001, p = 0.0031). Furthermore, these patients were significantly correlated with worse OS and RFS in univariate and multivariate analyses (OS; hazard ratio [HR] 6.22, 95% confidence interval [CI] 1.770–21.838, p = 0.0044/RFS; HR 3.24, 95% CI 1.012–13.206, p = 0.048).
Conclusion
Preoperative low serum TIBC levels may be a potential surrogate marker of long‐term survival after pancreatectomy for pancreatic cancer.
Keywords: pancreatic cancer, prognostic marker, total iron‐binding capacity
Preoperative low serum total iron‐binding capacity (TIBC) was associated with poorer overall survival and recurrence‐free survival after pancreatectomy for pancreatic cancer. These findings suggest that preoperative serum TIBC may serve as a simple surrogate marker for long‐term outcomes in patients undergoing pancreatectomy.
1. Introduction
Pancreatic cancer is a highly lethal malignancy with an increasing incidence and a high recurrence rate worldwide [1]. Chemotherapy and surgery are the primary treatment options; however, 10%–20% of patients are eligible for curative resection at diagnosis because of locally advanced or metastatic disease [2]. Although adjuvant therapy, newer drug combinations, and multimodal regimens appreciably extend survival, 80% of patients develop fatal recurrence [3]. Therefore, identifying risk factors associated with poor survival after pancreatectomy is essential for improving the outcomes of patients with pancreatic cancer.
To improve perioperative outcomes and survival rates, several studies have identified the prognostic factors of patients with pancreatic cancer. Nutritional and inflammatory markers are correlated with the prognosis of gastrointestinal cancer patients [4]. Several nutritional and inflammatory markers, such as the Glasgow prognostic score [5], neutrophil‐to‐lymphocyte ratio [6], and prognostic nutritional index [7], have been analyzed in pancreatic cancer patients. Total iron‐binding capacity (TIBC) is reported to be a useful nutritional marker [8]. Preoperative TIBC levels have been a valuable indicator of long‐term outcomes after gastrointestinal cancer surgeries [9, 10, 11]. However, no studies have demonstrated an association between preoperative TIBC levels and outcomes in pancreatic cancer patients after pancreatectomy.
The aim of the present study was to investigate the association between preoperative TIBC levels and long‐term outcomes after pancreatectomy for pancreatic cancer. Our findings may identify preoperative TIBC as a potential prognostic marker in patients with pancreatic cancer undergoing pancreatectomy. Furthermore, preoperative TIBC measurement may provide a useful indicator for assessing the nutritional status of patients with pancreatic cancer.
2. Patients and Methods
2.1. Patients and Transferrin Status Evaluation
A total of 236 patients underwent pancreatectomy for pancreatic cancer at the Kumamoto University Hospital, Japan between January 2010 and December 2021. Patients who lacked a preoperative transferrin test (n = 78) were excluded. A total of 158 patients who underwent pancreatectomy were eligible. TIBC levels are directly proportional to transferrin, which was calculated by summing serum iron and unsaturated iron‐binding capacity [12]. ROC analysis was performed using survival status at the end of the available follow‐up period as the binary outcome, and a TIBC cutoff value of 258 μg/dL was selected. Patients were divided into two groups according to the preoperative TIBC level (low TIBC, < 258 μg/dL; high TIBC, ≥ 258 μg/dL). We retrospectively compared patient characteristics and long‐term survival between the two groups using data from our institutional database. All patients gave written informed consent, and the Ethics Committee of Kumamoto University approved the study protocol. Our institutional Ethical Review Board approved this study (IRB No. 1291), and all procedures met the guidelines of the Declaration of Helsinki.
2.2. Treatment for Pancreatic Cancer
In our facility, individuals presenting with pancreatitis, cholangitis, or jaundice before pancreatic surgery undergo treatment involving either endoscopic stent placement or percutaneous transhepatic drainage coupled with tailored medication regimens based on individual characteristics. For each instance, we performed pancreatic resection with D2 lymph node dissection, guided by considerations such as tumor location or size, in accordance with established protocols [13]. The operative approach was determined according to patient characteristics, tumor location and extent, surgical complexity, and treatment era. Laparoscopic distal pancreatectomy for pancreatic cancer was introduced at our institution in 2018, and laparoscopic pancreaticoduodenectomy was introduced in 2020. During the early period of laparoscopic surgery, patients with relatively less locally advanced tumors were preferentially selected for laparoscopic surgery, whereas the choice of operative approach was based on the clinical judgment of the attending surgeons. The resectability status of pancreatic cancer was evaluated according to the 7th edition of the General Rules for the Study of Pancreatic Cancer, published by the Japan Pancreas Society [14]. Since 2016, we have implemented preoperative chemotherapy for borderline resectable pancreatic cancer, and since 2020, we have also introduced preoperative chemotherapy for resectable pancreatic cancer. Pancreatic cancers were staged according to the 7th edition of the American Joint Committee on Cancer (AJCC) for International Cancer Control (UICC) staging manual [15].
2.3. Statistical Methods
We conducted statistical comparisons between the groups using the chi‐square test. When analyzing unpaired samples, we used the Mann–Whitney U test. For a matrix containing fewer than five patients, we performed Fisher's exact test. We performed survival analysis using the Kaplan–Meier method to assess the distribution of survival time, and we used the log‐rank test when indicated. Associations between long‐term survival and clinicopathological features were evaluated using univariate and multivariate logistic regression analyses using odds ratios. The cut‐off value of C‐reactive protein (CRP), carcinoembryonic antigen (CEA), and carbohydrate antigen 19–9 (CA19‐9) was determined by median value. Factors with a probability level ≤ 0.1 were selected for subsequent multivariate analysis, and variables with a probability level < 0.05 were considered as independent risk factors. All statistical analyses were performed using JMP version 13.1 software (SAS Institute, Cary, NC, USA). All p values were two‐sided, and statistical significance was set at p < 0.05.
3. Results
3.1. Clinicopathological Features of Patients
Among the 236 patients who underwent pancreatectomy for pancreatic cancer, 158 patients who underwent a preoperative TIBC test were analyzed. Of all patients, 32 (20.3%) had low preoperative TIBC levels, and 126 (79.7%) had high preoperative TIBC levels. A low preoperative TIBC level was strongly associated with a higher rate of preoperative chemotherapy, higher CRP, lower albumin, and higher CEA compared to those in high TIBC levels (p = 0.046, 0.0068, 0.0006, 0.015, respectively). No significant differences were observed in other patient characteristics between the two groups (Table 1).
TABLE 1.
Patient characteristics who underwent pancreatectomy for pancreatic cancer according to preoperative TIBC.
| Variable | High TIBC (n = 126) | Low TIBC (n = 32) | p |
|---|---|---|---|
| Age (years), median (IQR) | 70.5 (63–76) | 71.0 (63.3–77.8) | 0.50 |
| Sex | 0.48 | ||
| Male | 74 (58.7%) | 21 (65.6%) | |
| Female | 52 (41.3%) | 11 (34.4%) | |
| BMI (kg/m2), median (IQR) | 21.2 (19.3–24.0) | 20.3 (18.9–20.3) | 0.060 |
| Diabetes mellitus | 60 (47.6%) | 17 (53.1%) | 0.58 |
| Preoperative chemotherapy | 26 (20.6%) | 12 (37.5%) | 0.046 * |
| Serum iron (μg/dL), median (IQR) | 82.0 (58.8–102.3) | 68.5 (34.3–100.0) | 0.074 |
| CRP (mg/dL), median (IQR) | 0.12 (0.04–0.33) | 0.31 (0.17–0.55) | 0.0068 * |
| Albumin (g/dL), median (IQR) | 4.0 (3.6–4.4) | 3.5 (3.3–3.9) | 0.0006 * |
| CEA (ng/mL), median (IQR) | 3.5 (1.9–5.4) | 4.9 (3.2–6.1) | 0.015 * |
| CA19‐9 (U/mL), median (IQR) | 44.5 (15.6–161.4) | 69.6 (18.5–187.1) | 0.32 |
| Operative procedure | 0.88 | ||
| Pancreaticoduodenectomy | 70 (55.6%) | 19 (59.4%) | |
| Distal pancreatectomy | 53 (42.1%) | 12 (37.5%) | |
| Total pancreatectomy | 3 (2.4%) | 1 (3.1%) | |
| Operative approach | 0.49 | ||
| Open | 105 (83.3%) | 25 (78.1%) | |
| Laparoscopic | 21 (16.7%) | 7 (21.9%) | |
| Operative time (min), median (IQR) | 424.5 (306.3–530.5) | 467.0 (392.0–588.3) | 0.11 |
| Bleeding (g), median (IQR) | 568.5 (304.0–1043.5) | 821.0 (354.3–1529.8) | 0.13 |
| Any morbidity of CDc ≥ II | 65 (51.6%) | 18 (56.3%) | 0.64 |
| Severe morbidity of CDc ≥ III | 32 (25.4%) | 7 (21.9%) | 0.68 |
| UICC stage (histopathological) | 0.48 | ||
| I | 25 (19.8%) | 3 (9.4%) | |
| IIA | 35 (27.8%) | 8 (25.0%) | |
| IIB | 59 (46.8%) | 19 (59.4%) | |
| III | 7 (5.6%) | 2 (6.3%) | |
| Histological type | 0.73 | ||
| Adenocarcinoma | 120 (95.2%) | 30 (93.8%) | |
| Adenosquamous carcinoma | 6 (4.8%) | 2 (6.3%) |
Abbreviations: BMI, Body mass index; CA19‐9, carbohydrate antigen 19–9; CDc, Clavien‐Dindo classification; CEA, carcinoembryonic antigen; CRP, C‐reactive protein; IQR, interquartile range; UICC, Union for International Cancer Control.
p < 0.05.
3.2. Overall Survival After Pancreatectomy
Patients with low preoperative TIBC levels had significantly poorer OS compared to that in high TIBC levels (p < 0.0001) (Figure 1A). In the univariate analysis, male, high preoperative CEA, low preoperative TIBC, open pancreatectomy, high UICC pathological stage, and comorbidity of diabetes mellitus were significantly correlated with poor OS (p = 0.048, 0.0028, 0.0007, 0.0002, 0.015, and 0.0016, respectively). In the multivariate analyses, a low preoperative TIBC level was an independent risk factor for poor OS (hazard ratio [HR] 6.22, 95% confidence interval [CI] 1.770–21.838, p = 0.0044). Open pancreatectomy was also an independent risk factor for poor OS (HR 6.74, 95% CI 2.254–20.126, p = 0.0006) (Table 2).
FIGURE 1.
Kaplan–Meier curves of (A) overall survival and (B) recurrence‐free survival after pancreatectomy for pancreatic cancer, in relation to their preoperative serum TIBC level. *p < 0.05.
TABLE 2.
Univariate and multivariate analysis for factors associated with worse overall survival in pancreatic cancer patients who underwent pancreatectomy.
| Factors | Objective variable | Control | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | p | HR | 95% CI | p | |||
| Age | ≥ 70 years | < 70 years | 0.95 | 0.496–1.826 | 0.89 | |||
| Sex | Male | Female | 1.94 | 1.005–3.777 | 0.048* | 1.63 | 0.753–3.527 | 0.22 |
| BMI | ≥ 25 kg/m2 | < 25 kg/m2 | 0.65 | 0.263–1.656 | 0.36 | |||
| CRP | ≥ 0.14 mg/dL | < 0.14 mg/dL | 1.26 | 0.658–2.413 | 0.49 | |||
| CEA | ≥ 3.85 ng/mL | < 3.85 ng/mL | 2.73 | 1.409–5.430 | 0.0028* | 2.10 | 0.948–4.646 | 0.068 |
| CA19‐9 | ≥ 48.8 U/mL | < 48.8 U/mL | 1.55 | 0.810–2.993 | 0.19 | |||
| Preoperative TIBC | Low | High | 5.25 | 1.919–18.511 | 0.0007* | 6.22 | 1.770–21.838 | 0.0044* |
| Operative approach | Open | Laparoscopic | 4.93 | 2.099–12.345 | 0.0002* | 6.74 | 2.254–20.126 | 0.0006* |
| Operative procedure | PD/TP | DP | 1.78 | 0.923–3.446 | 0.086 | 1.23 | 0.572–2.624 | 0.60 |
| UICC pathological stage | II/III | I | 2.79 | 1.221–6.555 | 0.015* | 1.45 | 0.534–3.931 | 0.47 |
| Histological type | Adenosquamous | Adenocarcinoma | 1.79 | 0.396–12.479 | 0.47 | |||
| Comorbidity of DM | Present | Absent | 2.24 | 1.162–4.413 | 0.016* | 1.90 | 0.874–4.140 | 0.10 |
Abbreviations: BMI, Body mass index; CA19‐9, carbohydrate antigen 19–9; CEA, carcinoembryonic antigen; CI, confidence interval; CRP, C‐reactive protein; DM, diabetes mellitus; DP, Distal pancreatectomy; HR, hazard ratio; PD, Pancreaticoduodenectomy; TIBC, total iron‐binding capacity; TP, Total pancreatectomy; UICC, Union for International Cancer Control.
p < 0.05.
3.3. Recurrence Free Survival After Pancreatectomy
Patients with low preoperative TIBC levels had significantly poorer recurrence‐free survival (RFS) compared to that in high TIBC level (p = 0.0031) (Figure 1B). In the univariate analysis, male, high preoperative CEA, low preoperative TIBC, open pancreatectomy, and high UICC pathological stage were significantly correlated with poor RFS (p = 0.038, 0.0060, 0.039, < 0.0001, and 0.0092, respectively). In the multivariate analysis, a low preoperative TIBC level was an independent risk factor for poor RFS (HR 3.24, 95% CI 1.012–13.206, p = 0.048). High preoperative CEA and open pancreatectomy were also independent risk factors for poor RFS (CEA; HR 2.55, 95% CI 1.109–6.163, p = 0.027/Open pancreatectomy; HR 6.27, 95% CI 2.312–18.178, p = 0.0003) (Table 3).
TABLE 3.
Univariate and multivariate analysis for factors associated with worse recurrence‐free survival in pancreatic cancer patients who underwent pancreatectomy.
| Factors | Objective variable | Control | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | p | HR | 95% CI | p | |||
| Age | ≥ 70 years | < 70 years | 1.04 | 0.508–2.1300 | 0.91 | |||
| Sex | Male | Female | 2.15 | 1.045–4.455 | 0.038* | 1.73 | 0.762–3.970 | 0.19 |
| BMI | ≥ 25 kg/m2 | < 25 kg/m2 | 0.92 | 0.349–2.742 | 0.88 | |||
| CRP | ≥ 0.14 mg/dL | < 0.14 mg/dL | 1.54 | 0.756–3.189 | 0.23 | |||
| CEA | ≥ 3.85 ng/mL | < 3.85 ng/mL | 2.79 | 1.335–6.069 | 0.0060* | 2.55 | 1.109–6.163 | 0.027* |
| CA19‐9 | ≥ 48.8 U/mL | < 48.8 U/mL | 1.82 | 0.890–3.821 | 0.101 | |||
| Preoperative TIBC | Low | High | 2.91 | 1.050–10.335 | 0.039* | 3.24 | 1.012–13.206 | 0.048* |
| Operative approach | Open | Laparoscopic | 5.60 | 2.376–13.599 | < 0.0001* | 6.27 | 2.312–18.178 | 0.0003* |
| Operative procedure | PD/TP | DP | 1.99 | 0.972–4.127 | 0.060 | 1.36 | 0.599–3.067 | 0.46 |
| UICC pathological stage | II/III | I | 3.16 | 1.336–7.440 | 0.0092* | 1.49 | 0.550–3.876 | 0.43 |
| Histological type | Adenosquamous | Adenocarcinoma | 1.05 | 0.232–7.395 | 0.95 | |||
| Comorbidity of DM | Present | Absent | 1.30 | 0.637–2.683 | 0.47 | |||
Abbreviations: BMI, Body mass index; CA19‐9, carbohydrate antigen 19–9; CEA, carcinoembryonic antigen; CI, confidence interval; CRP, C‐reactive protein; DM, diabetes mellitus; DP, Distal pancreatectomy; HR, hazard ratio; PD, Pancreaticoduodenectomy; TIBC, total iron‐binding capacity; TP, Total pancreatectomy; UICC, Union for International Cancer Control.
p < 0.05.
4. Discussion
In the present study, we show that preoperative TIBC levels are significantly associated with poor long‐term survival in patients who underwent pancreatectomy for pancreatic cancer.
Transferrin, which is proportional to TIBC, is a representative rapid‐turnover protein that is synthesized in the liver, with a half‐life of 7 days [16]. Thus, TIBC reflects real‐time nutritional status. Although TIBC is a nutritional marker, few studies have demonstrated an association between preoperative TIBC levels and postoperative complications. Low preoperative transferrin levels have been reported to be associated with an increased risk of postoperative infectious complications after total knee arthroplasty [17]. We previously reported that patients with low preoperative TIBC levels experienced significantly more frequent postoperative pneumonia after esophagectomy for esophageal cancer [9]. With regard to the relationship between serum transferrin levels and survival, serum transferrin was demonstrated to be an independent risk factor for poor prognosis in patients with severe alcoholic hepatitis [18]. In the gastrointestinal surgeries, it was elucidated that patients with low preoperative TIBC levels were significantly correlated with worse survival after esophagectomies [9], colorectal cancer surgeries [10], and hepatectomies [11]. In the current study, we showed that the preoperative TIBC level is a potential indicator of OS and RFS after pancreatectomy for pancreatic cancer.
Several studies have demonstrated that the risk factors lead to poor survival of patients with pancreatic cancer. Tumor size at diagnosis, high CA19‐9 levels, high Charlson age‐comorbidity index, and poor tumor differentiation grade are risk factors of worse long‐term outcomes in pancreatic cancer patients [19]. Preoperative nutritional status, evaluated by serum albumin, prognostic nutritional index (PNI), and controlling nutritional status (CONUT) score, is also a critical factor of long‐term outcomes after pancreatectomy [20, 21, 22]. Matsumoto et al. elucidated that a low level of prealbumin, one of the rapid‐turnover proteins, was an independent risk factor for poor OS after pancreatectomy for pancreatic cancer (HR 1.97, 95% CI 1.095–3.559, p = 0.024) [23]. In the current study, we concluded that low TIBC level was an independent risk factor for poor OS after pancreatectomy for pancreatic cancer (HR 6.22, 95% CI 1.770–21.838, p = 0.0044) and had a higher HR of OS than prealbumin in Matsumoto's study. These data indicate that TIBC may be a better prognostic indicator of OS after pancreatectomy than prealbumin.
Pancreatic cancer is one of the cancer types with the highest risk of malnutrition due to cancer cachexia, pancreatic exocrine insufficiency, and impaired oral intake [24]. Thus, appropriate perioperative nutritional management is essential to improve outcomes after pancreatectomy for pancreatic cancer. Several studies have shown that perioperative nutritional intervention, such as an immune‐enhancing diet or enteral nutrition via jejunostomy, could improve postoperative outcomes after pancreatectomy [25, 26]. Nutritional screening and assessment are important for providing optimal perioperative nutritional support. Preoperative TIBC levels can be measured easily and quickly and may predict postoperative outcomes after pancreatectomy. Therefore, measurement of preoperative TIBC levels may be useful for evaluating the nutritional status of patients with pancreatic cancer.
Beyond its role as a nutritional marker, TIBC is closely related to iron homeostasis because it largely reflects circulating transferrin levels [12]. Transferrin delivers iron to cells through transferrin receptor 1 (TFRC), thereby regulating intracellular iron availability. In pancreatic cancer, increased intracellular iron may promote lipid peroxidation and ferroptosis, an iron‐dependent form of regulated cell death [27]. Thus, the TIBC–transferrin–TFRC axis may influence intracellular iron levels and ferroptosis susceptibility. However, as the present study did not directly evaluate intratumoral iron metabolism or ferroptosis‐related pathways, the biological mechanisms underlying the observed association remain unclear and warrant further investigation.
The present study has several limitations. First, this was a retrospective study conducted at a single institution. Second, 78 excluded patients due to insufficient data might have led to selection bias. Third, the observation period was relatively long, which may have led to historical bias. During the study period, preoperative chemotherapy was introduced for patients with borderline resectable pancreatic cancer in 2016 and was subsequently extended to those with resectable pancreatic cancer in 2020. These changes in treatment strategies over time may have influenced the study outcomes. Fourth, the relatively small cohort size resulted in wide confidence intervals for several hazard ratios, indicating limited statistical precision. Therefore, the findings of this study should be considered hypothesis‐generating rather than definitive. Larger prospective, multicenter studies are warranted to validate our findings.
In conclusion, preoperative low serum TIBC levels may be a potential surrogate marker of poor long‐term survival after pancreatectomy for pancreatic cancer.
Author Contributions
Taishi Yamane: writing – original draft. Hiromitsu Hayashi: writing – review and editing. Hiroshi Sawayama: conceptualization. Takashi Matsumoto: methodology. Toru Takematsu: investigation. Takanobu Yamao: formal analysis. Yuki Kitano: supervision. Tatsunori Miyata: supervision. Hirohisa Okabe: supervision. Masaaki Iwatsuki: writing – review and editing, supervision.
Funding
Japan Agency for Medical Research and Development (AMED), JP256f0137011.
Ethics Statement
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.
Consent
The ethics committee at our hospital admitted the present study procedure and waived the requirement for written informed consent (Registry Number: 1291).
Conflicts of Interest
Masaaki Iwatsuki is an editorial member of Annals of Gastroenterological Surgery.
Acknowledgments
This research was supported by AMED under Grant Number JP256f0137011.
Data Availability Statement
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.