Abstract
Purpose
To evaluate the prognostic significance of sarcopenia and systemic inflammatory markers in patients with surgically resected biliary tract cancer (BTC).
Methods
Between July 2010 and December 2022, 146 patients were recruited. Sarcopenia was assessed using the psoas muscle index. Preoperative inflammatory markers were used to calculate the prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio. Cox regression analysis was performed to determine prognostic factors for overall survival (OS) and recurrence-free survival (RFS). P < 0.05 was considered statistically significant.
Results
Sixty-four patients had sarcopenia. Sarcopenia was associated with body mass index (< 22 kg/m2), lymph node metastasis, and low PNI (< 42). R1/R2 resection (P = 0.02), sarcopenia (P < 0.001), lymph node metastasis (P = 0.007), intrahepatic cholangiocarcinoma (P < 0.001), and low PNI (P = 0.01) were independent predictors of OS, while male sex (P = 0.04), R1/R2 resection (P < 0.001), lymph node metastasis (P = 0.005), intrahepatic cholangiocarcinoma (P < 0.001), tumor differentiation (other than well; P = 0.003), and low PNI (P = 0.03) were independent predictors of RFS. Patients were stratified into no sarcopenia and high PNI (≥ 42; A), sarcopenia or low PNI (B), and sarcopenia and low PNI (C) groups. Group C had worse OS than the other two groups (P < 0.001 and P = 0.02, respectively).
Conclusion
Sarcopenia is associated with the PNI. Sarcopenia and the PNI are independent prognostic factors among patients with resected BTC. Sarcopenia may have better prognostic value when combined with the PNI.
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Introduction
Biliary tract cancer (BTC), including gallbladder carcinoma, intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, distal cholangiocarcinoma, and ampullary carcinoma, is a rare aggressive malignancy that has been increasing in incidence in recent decades [1]. Resection is the only curative treatment for BTC. However, recurrence is a major concern [2]. Most patients are not eligible for surgical resection, because of the advanced stage of the disease at the time of diagnosis. Despite advances in surgical techniques and adjuvant chemotherapy, the prognosis remains poor [3]. Preoperative prognostic factors for BTC may allow better preoperative risk–benefit assessment and permit patient stratification for precision medicine [4].
Sarcopenia is characterized by the loss of skeletal muscle mass and strength. It is associated with aging, as well as pathological conditions, such as liver cirrhosis, renal failure, and cancer. The importance of sarcopenia in cancer has been recognized as low muscularity is an independent predictor of poor prognosis in various cancers [5]. Sarcopenia is associated with overall survival (OS) in patients with BTC [6]. Therefore, the prediction and early diagnosis of sarcopenia are crucial for the prognosis of patients with BTC.
Sarcopenia is associated with inflammation in cancer, as well as aging [7]. Several studies have shown that systemic inflammation and nutritional status are associated with poor prognosis in patients with cancer [8, 9]. Several markers have been used to assess systemic inflammation in the clinic, including the prognostic nutritional index (PNI), Glasgow Prognostic Score, C-reactive protein-to-albumin ratio, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio [10, 11].
Patients with metastatic BTC and hepatocellular carcinoma with high systemic inflammation and sarcopenia have worse OS [12, 13]. However, the relationship between systemic inflammation and sarcopenia in patients with surgically resected BTC has not been well studied. This study aimed to evaluate the prognostic significance of sarcopenia and systemic inflammatory markers in patients with surgically resected BTC.
Materials and Methods
Patients
A total of 147 consecutive patients who underwent surgical resection for BTC at our institution between July 2010 and December 2022 were retrospectively reviewed. BTC, including gallbladder carcinoma, intrahepatic cholangiocarcinoma, distal cholangiocarcinoma, ampullary carcinoma, and perihilar cholangiocarcinoma, was confirmed by pathological examination. One patient who died of heart failure due to arrhythmia on postoperative day 18 was excluded. A total of 146 patients who underwent surgical resection for BTC were analyzed.
Data Collection
Data on demographic characteristics (age at surgery and sex), laboratory tests (serum albumin/C-reactive protein levels, platelet/neutrophil/lymphocyte counts, total bilirubin, conjugated bilirubin, and tumor markers), comorbidities (hypertension, diabetes mellitus, cardiac disease, and stroke), preoperative cholangitis, surgical procedure (type of resection), operative time, blood loss, transfusion, tumor stage (Union for International Cancer Control Tumor–Node–Metastasis classification [eight edition]), tumor differentiation, and postoperative adjuvant chemotherapy were obtained from patients’ medical records. Liver resections were classified according to the Brisbane 2000 Terminology of Liver Anatomy and Resections [14]. Curative (R0) resection was defined as complete removal of all macroscopic nodules with microscopically clear margins. R1 and R2 resections were defined as microscopically or macroscopically positive margins, respectively. Complications were defined according to the Clavien–Dindo classification [15]. In this study, postoperative complications were defined as complications of Clavien–Dindo Grade ≥ IIIa. Postoperative mortality was defined as death from any cause within 30 days after surgery.
Sarcopenia Definition
Sarcopenia was assessed using the psoas muscle index, an alternative measurement of sarcopenia that has been adopted by the Japan Society of Hepatology [16]. Preoperative computed tomography imaging was performed within 1 month before surgery using a multidetector computed tomography scanner. Using preoperative computed tomography at the level of the caudal end of the third lumbar vertebra, the cross-sectional area of the bilateral psoas muscles was measured by manual tracing. The psoas muscle index was calculated as the cross-sectional area of the bilateral psoas muscles (cm2) divided by height squared (m2). A low psoas muscle index was considered a proxy for low muscle volume [16].
Because the psoas muscle index range differs between men and women, different cutoff values were established using receiver operating characteristic curves. The optimal cutoff values were determined based on the best accuracy in relation to outcome. The cutoff values for psoas muscle index in men and women were 5.10 and 3.69 cm2/m2, respectively (area under the receiver operating characteristic curve—0.587 and 0.625, respectively).
Systemic Inflammatory Markers
Peripheral venous blood samples were collected within 2 weeks before surgery. The PNI was calculated as 10 × serum albumin (g/dL) + 0.05 × total lymphocyte count (/mm3) [17]. The Glasgow Prognostic Score was defined as follows: 0, normal albumin ≥ 3.5 g/dL and C-reactive protein ≤ 1.0 mg/dL; 1, low albumin < 3.5 g/dL or high C-reactive protein > 1.0 mg/dL; and 2, low albumin < 3.5 g/dL and high C-reactive protein > 1.0 mg/dL [18]. The C-reactive protein-to-albumin ratio was calculated as C-reactive protein (mg/dL) divided by albumin (g/dL) [19]. The neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios were calculated by dividing the neutrophil and platelet counts by the lymphocyte count, respectively [10, 11].
Follow-Up
All patients underwent routine follow-up until December 2022. Postoperative follow-up included medical history (symptoms and physical examination), laboratory tests, and imaging studies performed every 6 months for ≥ 5 years. Patients with lymph node metastasis or who underwent R1/R2 resection received postoperative adjuvant chemotherapy (tegafur/gimeracil/oteracil) for approximately 6 months. None of the patients received neoadjuvant chemotherapy.
Outcomes
The relationships between clinicopathological characteristics and OS and RFS were analyzed using univariate and multivariate Cox regression analyses. The duration between surgery and death or the last follow-up was defined as OS. The duration between surgery and recurrence which confirmed by radiology imaging was defined as recurrence-free survival (RFS).
Statistical Analysis
All data were blinded before analysis. Continuous data were presented as median (interquartile range). Categorical data were presented as numbers (percentage). Univariate analysis was performed using the Mann–Whitney U test and chi-square test. Diagnostic accuracy was determined using the area under the receiver operating characteristic curve. The optimal cutoff values of systemic inflammatory markers were determined by maximizing the Youden index (sensitivity + specificity − 1). OS was estimated using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards model. Prognostic factors that were significant in the univariate analysis were included in the multivariate analysis. All statistical analyses were conducted using JMP 11 (SAS Institute, Cary, NC, USA). P < 0.05 was considered statistically significant.
Results
Patient Characteristics
Patient characteristics are summarized in Table 1. The median age was 74 (range, 38–92) years. 64 patients had sarcopenia. 43 patients had gallbladder carcinoma; 33, intrahepatic cholangiocarcinoma; 31, distal cholangiocarcinoma; 23, ampullary carcinoma; and 16, perihilar cholangiocarcinoma. Curative (R0) resection was achieved in 125 patients. Surgical procedures included liver resection in 67 patients (hemihepatectomy [N = 36], subsegmentectomy [N = 11], liver bed resection [N = 8], sectionectomy [N = 7], trisectionectomy [N = 4], and partial hepatectomy [N = 1]), pancreaticoduodenectomy in 52, cholecystectomy in 24, hepatopancreaticoduodenectomy in two, and bile duct resection without hepatectomy in one. Postoperative complications were observed in 51 patients: pancreatic fistula in 29, bile leakage in nine, abdominal abscess in eight, pleural effusion and chylous ascites in two each, and abdominal bleeding in one. The optimal cutoff values for the PNI, Glasgow Prognostic Score, C-reactive protein-to-albumin ratio, platelet-to-lymphocyte ratio, and neutrophil-to-lymphocyte ratio were 42 (sensitivity, 31.3%; specificity, 83.0%; area under the receiver operating characteristic curve, 0.560; and 95% confidence interval, 0.467–0.625), 1 (sensitivity, 26.6%; specificity, 80.3%; area under the receiver operating characteristic curve, 0.530; and 95% confidence interval, 0.462–0.623), 0.125 (sensitivity, 51.9%; specificity, 69.5%; area under the receiver operating characteristic curve, 0.590; and 95% confidence interval, 0.497–0.680), 106 (sensitivity, 79.7%; specificity, 31.8%; area under the receiver operating characteristic curve, 0.550; 95% confidence interval, 0.450–0.638), and 1.59 (sensitivity, 26.6%; specificity, 80.5%; area under the receiver operating characteristic curve, 0.467; and 95% confidence interval, 0.372–0.560), respectively.
Relationship Between Clinicopathological Characteristics and Sarcopenia
Patients were stratified into two groups according to the presence (N = 64) or absence (N = 82) of sarcopenia. Clinicopathological characteristics were compared between the two groups. Body mass index in the sarcopenia group was lower than that in the non-sarcopenia group [20.8 (18.9–23.3) vs. 23.6 (22.1–26.2) kg/m2, respectively; P < 0.001]. PNI was also lower in the sarcopenia group than in the non-sarcopenia group [44.3 (40.0–48.6) vs. 48.5 (42.9–52.3), respectively; P = 0.009]. There were more patients with preoperative cholangitis in the sarcopenia group than in the non-sarcopenia group. The incidence of lymph node metastasis was higher in the sarcopenia group than in the non-sarcopenia group (46.9% vs. 29.3%, respectively; P = 0.03) (Table 2).
Univariate and Multivariate Analyses of Prognostic Factors for OS
The median OS was 47 (range, 6–147) months. The 1-, 3-, and 5-year OS rates were 87.7%, 57.2%, and 46.1%, respectively. In the Kaplan–Meier analysis, the sarcopenia group had worse OS than the non-sarcopenia group (P = 0.001; Fig. 1a), and the low PNI (< 42) group had worse OS than the high PNI (≥ 42) group (P = 0.007; Fig. 1b).
Table 3 shows the relationship between clinicopathological characteristics and OS after surgical resection. Univariate analysis showed that male sex, R1/R2 resection, sarcopenia, lymph node metastasis, intrahepatic cholangiocarcinoma, T stage ≥ 3, tumor differentiation, low PNI, C-reactive protein-to-albumin ratio ≥ 0.125, and carbohydrate antigen 19–9 levels ≥ 20 U/mL were associated with poor OS. R1/R2 resection (P = 0.02), sarcopenia (P < 0.001), lymph node metastasis (P = 0.007), intrahepatic cholangiocarcinoma (P < 0.001), and low PNI (P = 0.01) were independent predictors of OS in the multivariate analysis.
Univariate and Multivariate Analyses of Prognostic Factors for RFS
The median RFS was 60 (range, 6–147) months. The 1-, 3-, and 5-year RFS rates were 68.1%, 55.4%, and 48.9%, respectively.
Table 4 shows the relationship between clinicopathological characteristics and RFS after surgical resection. Univariate analysis showed that male sex, R1/R2 resection, sarcopenia, lymph node metastasis, intrahepatic cholangiocarcinoma, T stage ≥ 3, tumor differentiation, low PNI, C-reactive protein-to-albumin ratio ≥ 0.125, carbohydrate antigen 19–9 levels ≥ 20 U/mL, and postoperative adjuvant chemotherapy were associated with poor RFS. Male sex (P = 0.04), R1/R2 resection (P < 0.001), lymph node metastasis (P = 0.005), intrahepatic cholangiocarcinoma (P < 0.001), tumor differentiation (other than well; P = 0.003), and low PNI (P = 0.03) were independent predictors of RFS in the multivariate analysis.
Impact of Sarcopenia and PNI on OS
Sarcopenia and PNI were independent predictors of OS in patients with BTC. Patients were stratified into three groups according to these two factors: Group A, no sarcopenia and high PNI; Group B, sarcopenia or low PNI; and Group C, sarcopenia and low PNI. In the Kaplan–Meier analysis, Group C had worse OS than the other two groups (P < 0.001 and P = 0.02, respectively) (Fig. 2).
As sarcopenia and PNI are strongly associated with OS, we performed a multivariate analysis of sarcopenia and PNI. Multivariate analysis showed that sarcopenia and low PNI and sarcopenia or low PNI were independent predictors of OS (P < 0.001 and P = 0.047, respectively) (Table 5).
Subgroup Analysis According to Tumor Location
The impact of sarcopenia and PNI on OS was also analyzed in relation to tumor location. Patients with gallbladder carcinoma and intrahepatic cholangiocarcinoma in Group C had worse OS than those in the other two groups (both, P < 0.001; Fig. 3). For patients with distal cholangiocarcinoma, ampullary carcinoma, and perihilar cholangiocarcinoma, the impact of sarcopenia and PNI on OS was not significant.
Discussion
In this study, we showed that sarcopenia and low PNI are independent predictors of poor OS in patients with surgically resected BTC. Patients in Group C had the worst OS among the three groups. To our knowledge, this is the first study to show that sarcopenia accompanied by low PNI is associated with poor OS in patients with BTC.
Sarcopenia is a hallmark of cancer cachexia and is a major factor leading to increased morbidity and mortality in patients with advanced gastrointestinal cancer [20]. The role of sarcopenia as a prognostic marker remains controversial. Therefore, there is an urgent need to investigate the prognostic significance of sarcopenia in patients with BTC. In this study, multivariate analysis showed that sarcopenia is associated with OS but not RFS. A previous study [6] confirmed that sarcopenia is an independent predictor of OS and RFS after surgical resection of BTC. Yoon et al. [21] analyzed the significance of sarcopenia in BTC and showed that sarcopenia (a low skeletal muscle index) was not associated with poor OS. Another study [13] showed that sarcopenia alone did not predict OS and RFS in multivariate analysis. However, sarcopenia and high neutrophil-to-lymphocyte ratio (> 3) were associated with poor OS and progression-free survival in patients with metastatic BTC. It is possible that BTC is more affected by tumor- than by patient-related factors (such as sarcopenia). Our findings support the prognostic value of sarcopenia in surgically resected BTC.
Systemic inflammation is a significant factor that can predict the prognosis of various cancers. Several inflammatory markers (Glasgow Prognostic Score, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio) are associated with poor prognosis in patients with BTC [13, 22, 23]. PNI, a marker of nutritional status and systemic inflammation, is based on serum albumin and lymphocyte count, both of which can be easily obtained from routine preoperative blood tests. Several studies [24, 25] have shown that the PNI can be used as a prognostic marker in patients with BTC. We previously investigated the prognostic significance of PNI in patients with surgically resected BTC and demonstrated its potential clinical application [22]. In this study, we obtained similar results with PNI. The mechanism(s) underlying the prognostic significance of PNI in patients with BTC have been discussed previously.
Patients with sarcopenia accompanied by inflammation have faster disease progression and worse OS than those without sarcopenia and inflammation. The relationship between sarcopenia and systemic inflammatory markers has attracted increasing attention. There is a strong correlation between systemic inflammatory markers and catabolic pathway activation [26]. Tumor necrosis factor and interleukin 6, which are released by the tumor and surrounding cells, can suppress protein synthesis, and stimulate protein degradation. The tumor itself also promotes inflammation, which facilitates tumor progression. The secretion of proinflammatory myokines induces muscle degeneration and exacerbates systemic inflammation [27]. A previous study [28] suggested that inflammation causes malnutrition, resulting in impaired immune responses and reduced muscle strength. Inflammation and malnutrition jointly lead to sarcopenia. In this study, patients with sarcopenia had low PNI and advanced disease compared to those without sarcopenia, suggesting that sarcopenia is associated with nutritional–inflammation status and tumor progression. Our findings are consistent with those of the aforementioned studies. Sarcopenia may have better prognostic value in patients with surgically resected BTC when combined with PNI.
In the subgroup analysis, sarcopenia and low PNI were associated with poor OS in patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma but not distal cholangiocarcinoma, ampullary carcinoma, and perihilar cholangiocarcinoma. The reason may be that intrahepatic cholangiocarcinoma and gallbladder carcinoma have relatively high R0 resection rates. The R0 resection rates of intrahepatic cholangiocarcinoma and gallbladder carcinoma were 97.1% and 86.0%, respectively, while those of distal cholangiocarcinoma, ampullary carcinoma, and perihilar cholangiocarcinoma were 80.0%, 95.1%, and 62.5%, respectively. Intrahepatic cholangiocarcinoma and gallbladder carcinoma may be more affected by patient-related factors (such as sarcopenia and PNI), whereas distal cholangiocarcinoma, ampullary carcinoma, and perihilar cholangiocarcinoma may be more affected by tumor-related factors and surgical outcomes.
Kaido et al. [29] reported the impact of nutritional therapy on prognosis after liver transplantation in patients with sarcopenia. Mayo et al. [30] reported that preoperative rehabilitation is effective in reducing postoperative complications in patients with various cancers. Supportive therapies focusing on perioperative nutrition and rehabilitation may be applicable to patients with surgically resected BTC. However, the efficacy of such therapies requires further evaluation in prospective studies.
This study has several limitations related to its single-center, retrospective design. The sensitivity, specificity, and areas under the receiver operating characteristic curves of the psoas muscle index and PNI were low. Further multicenter prospective studies are needed to validate our findings. Sarcopenia should be diagnosed not only by the detection of low muscle mass but also by reduced muscle strength. The diagnosis of sarcopenia in this study may not have been accurate enough.
Conclusions
Sarcopenia and low PNI are associated with poor OS in patients with surgically resected BTC. Both sarcopenia and PNI are independent predictors of OS in patients with BTC. Nutritional therapy and rehabilitation may enhance the survival of cancer patients with sarcopenia and inflammation.
Data Availability
No datasets were generated or analyzed during the current study.
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Conceptualization: Masashi Utsumi, Masaru Inagaki, Koji Kitada, Naoyuki Tokunaga, Kosuke Yonoki, Yuya Sakurai, Hiroki Okabayashi, Ryosuke Hamano, Hideaki Miyasou, Yousuke Tsunemitsu, and Shinya Otsuka. Formal analysis and investigation: Masashi Utsumi, Masaru Inagaki, Koji Kitada, and Naoyuki Tokunaga. Writing—original draft preparation: Masashi Utsumi. Writing—review and editing: Masaru Inagaki.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of the National Hospital Organization Fukuyama Medical Center, Fukuyama, Hiroshima, Japan (No. ERB2022027).
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Utsumi, M., Inagaki, M., Kitada, K. et al. Prognostic Significance of Sarcopenia and Systemic Inflammatory Markers in Biliary Tract Cancer: A Retrospective Cohort Study. J Gastrointest Canc 55, 888–899 (2024). https://doi.org/10.1007/s12029-024-01034-6
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DOI: https://doi.org/10.1007/s12029-024-01034-6