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An exploratory study of serum creatine kinase as a prognostic marker for patients with resectable pancreatic cancer: looking into the relationship with body composition
Nutrition Journal volume 24, Article number: 22 (2025)
Abstract
Background
Among cancer patients, pancreatic cancer patients have the highest rate of sarcopenia, which is a critical prognostic factor. Serum creatine kinase (CK) is closely related to skeletal muscle mass and has been reported to decline with the progression of cancer. This study investigated whether preoperative serum CK is associated with the survival of patients with pancreatic cancer.
Methods
Data were obtained from patients with pathologically confirmed pancreatic cancer between June 2016 and March 2022. The prognostic significance of CK was analyzed based on sex-stratified groups. The Kaplan-Meier method was used to compare overall survival (OS) and disease-free survival (DFS). Multivariate Cox proportional hazards models were used to determine prognostic factors. Body composition was analyzed based on preoperative abdominal CT images to explore the sex-specific associations between skeletal muscle area (SMA) and serum CK levels.
Results
A total of 166 patients were included in this study. Sarcopenia was presented in 70 patients (42.2%). A low serum CK level showed a significant correlation with the diagnosis of sarcopenia in male patients (P = 0.026). The levels of CK did not predict the outcome in female patients, while a low preoperative CK was notably linked to shorter OS in male patients (median OS: 15 months vs. 33 months, P = 0.011; median DFS: 5 months vs. 14 months, P = 0.007). Multivariate analyses further confirmed the effect of CK in predicting OS (CK>44 IU/L, HR:0.226, 95% CI:0.107–0.478, P < 0.001) and DFS (CK>44 IU/L, HR:0.272, 95% CI:0.139–0.529, P < 0.001) of male patients. Correlation analysis revealed a significant association between SMA and CK levels in male patients (r = 0.225, P = 0.025), and such a correlation was not observed in female patients (r = 0.088, P = 0.478).
Conclusion
The pretherapeutic CK may represent a simple marker for predicting poor survival in male patients with resectable pancreatic cancer, thereby aiding in the selection of therapeutic strategies.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer death worldwide [1]. It results in 466,000 annual deaths, nearly as many as the number of new cases (496,000). Because of delayed diagnosis and unsatisfactory response to treatments, pancreatic cancer (PC) is the tumor with the worst prognosis, with a 5-year relative survival rate of approximately 10% [2].
According to the IMPACT study conducted in Italy [3], nearly 73.0% of patients with advanced-stage PC exhibited sarcopenia. The European Working Group on Sarcopenia in Older People (EWGSOP) defined sarcopenia as a presence of both low muscle mass and low muscle function [4]. It is a complex, multifactorial disorder that involves inflammation, protein catabolism, insulin resistance, and anorexic effects. In addition to these etiologies, pancreatic endocrine and exocrine insufficiencies are the two special pathological factors that exacerbate pancreatic cancer-related sarcopenia [5]. For patients with PC, sarcopenia is an established adverse prognostic factor for both operable and advanced PC patients [3, 6], even in overweight or obese patients [7]. Assessment of skeletal muscle mass before initial treatment helps identify those patients most likely to benefit from adjuvant or neoadjuvant therapy [8]. In the clinical setting, measuring muscle mass for cancer patients remains far from routine because the tools used to measure skeletal muscle mass (CT scan, dual energy X-ray absorptiometry, or bioimpedance) are limited by their accessibility, repeatability, or irradiation [9]. The need to monitor sarcopenia supports the quest for biomarkers that might reflect the skeletal muscle atrophy process.
Serum creatine kinase (CK) is a common marker related to myopathies and has been reported to be correlated with skeletal muscle mass [10, 11]. Several studies assessed the relationship between prognosis and CK levels in patients with lung [10], esophageal [12], or gastric cancer [13], and their results showed a promising prognostic value of serum CK. Our previous study [14] indicated a lower serum CK in PC patients than in patients with benign pancreatic tumors, but the relationship between serum CK and survival in pancreatic cancer patients has yet to be evaluated, limiting its application in these patients.
Notably, existing studies based on sex-specific subgroup analyses have shown a consistent finding that the prognostic significance of CK is restricted to male patients [12, 13, 15]. The mechanism by which CK’s prognostic role exhibits sexual dimorphism remains unclear, and there is a lack of in-depth research in this area. The reference intervals of serum CK for males and females are also different. Hence, sex-stratified analyses were adopted in the current study.
This study aimed to: (1) assess the significance of preoperative serum CK levels in prognostic prediction for patients with surgically resected pancreatic cancer; (2) evaluate the association between body composition and serum CK in patients with resectable PC.
Materials and methods
Study design and patient selection
We retrospectively reviewed patients with PC who were diagnosed and followed up at Fujian Medical University Union Hospital from June 2016 to March 2022. Patients with PC who had undergone curative resection via pancreaticoduodenectomy, total pancreatectomy, or distal pancreatectomy were included in this study. The following exclusion criteria were applied: (1) history of malignancy; (2) missing data on preoperative serum CK; (3) stroke; (4) acute myocardial infarction or myocardopathy; and (5) progressive muscular dystrophy, polymyositis, or dermatomyositis. To investigate the prognosis value of CK, patients were further divided into high CK and low CK groups using sex-specific CK cutoff values. These values were identified with the help of X-tile software (Version 3.6.1, Yale University) [16], with 44 IU/L for male patients and 37 IU/L for female patients. A flow chart of the study is shown in Fig. 1. All data were obtained from the hospital’s electronic records. Blood was collected for albumin, CK, and CK-MB measurement in the morning while subjects were fasting, and these parameters were measured using Roche Cobas C702 Analyzers (Roche Diagnostics GmbH, Mannheim, Germany). The prognostic nutritional index (PNI) was calculated using the formula: serum albumin level (g/L) + 0.005 × total lymphocyte count (per mm3) [17]. A PNI value of at least 50 was defined as normal. Values below 50 were categorized as follows: 45–49.9 for mild malnutrition, 40–44.9 for moderate to severe malnutrition, and less than 40 for serious malnutrition. This study was approved by the Ethics Committee of Fujian Medical University Union Hospital (Approval No.2023KY080) and was conducted in accordance with the Declaration of Helsinki.
CT-based body composition analysis and definition of Sarcopenia
Preoperative CT scans were used to assess the skeletal muscle mass of patients in this study with the support of sliceOmatic software (v.5.Tomovision, Montreal, Quebec, Canada). In detail, a single slice of an unenhanced CT scan at the third lumbar vertebra (L3) level was extracted from the picture archiving and communication system (PACS), since skeletal muscle area at this level is closely related to whole-body skeletal muscle [18]. The skeletal muscle area (SMA) was measured with a range of attenuation values for muscle set between − 29 and + 150 Hounsfield unit (HU). Areas of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) tissue were measured using thresholds of – 190 to – 30 HU and − 150 to – 50 HU, respectively [6].
The skeletal muscle index (SMI) was calculated by dividing SMA by height in meters squared, representing a normalized index of skeletal muscle mass. Sex-specific SMI cutoff values for sarcopenia were determined as 45.16 cm2/m2 for males and 34.65 cm2 /m2 for females, according to a study of PC in an Asian population [19].
Treatments and follow-up
Patients with resectable PC underwent pancreaticoduodenectomy, distal pancreatectomy, or total pancreatectomy according to the location of the tumor. Chemotherapy was recommended for postoperative patients and the chemotherapy regimens were as described in the guidelines [20]. Follow-up was conducted routinely through outpatient visits, hospitalization, and/or telephone. Overall survival (OS) was defined as the time from the operation to death from any cause or last follow-up, while disease-free survival (DFS) was defined as the time from the operation to the date of disease recurrence.
Statistical analysis
The intragroup differences in categorical variables or continuous variables were compared using the chi-square test and the Mann–Whitney U test, respectively. The median OS was calculated by the Kaplan–Meier method and the log-rank test was applied for the analysis of intragroup differences. To identify independent prognostic factors, variables with P value < 0.1 in univariable analyses were further subjected to multivariable analyses using Cox regression models. The correlations between serum CK and body composition metrics were examined by Pearson’s correlation or Spearman’s rank correlation analysis. IBM SPSS Statistics version 25 (IBM SPSS Inc., Chicago, USA) and R software (version 4.2.1, R Foundation for Statistical Computing, Vienna, Austria) were used for statistical analyses. A two-sided P value < 0.05 was considered significant.
Results
Patient characteristics
A total of 166 patients with resectable PC were ultimately reviewed and analyzed. Their clinical features are outlined in Table 1. Males and females constituted 59.6% and 40.4% of the patients, respectively. Most of the tumors were located in the head/neck of the pancreas (69.3%). According to the TNM staging, 42.2% of the patients were in stage II followed by 30.1% in stage I. A total of 70 patients had sarcopenia (42.2%).
Clinicopathological characteristics associated with CK levels
Patients were categorized into high CK and low CK groups using sex-specific CK cutoff values (44 IU/L for male patients; 37 IU/L for female patients), and the baseline characteristics were compared between the groups (Table 2). For male patients, demographic (age, BMI) and tumor-related characteristics (CA19-9, TNM stage, tumor location, differentiation, lymphatic invasion, and vascular invasion) were comparable between the high CK and low CK groups, while the sarcopenia rate was significantly higher in the low CK group than in the high CK group (72.2% vs. 43.2%). In female patients, the high CK and low CK groups shared similar clinicopathological characteristics.
Relationships of DFS and OS with serum CK levels
The median overall survival after surgery for the entire cohort was 30.0 months. Overall 1-, 3-, and 5-year survival rates were 94.5%, 43.2%, and 11.1%, respectively. Survival of patients with different CK levels was depicted using survival curves, including OS and DFS (Fig. 2). In male patients, the log-rank test revealed that OS and DFS were significantly shorter in the low CK group than in the high CK group (median OS: 15 months vs. 33 months, P = 0.011; median DFS: 5 months vs. 14 months, P = 0.007). In female patients, OS and DFS did not differ between the low and high CK groups (median OS: 26 months vs. 31 months, P = 0.81; median DFS: 11 months vs. 11 months, P = 0.52).
Prognostic value of CK for male patients after adjusting the effect of confounding factors by multivariate analysis
The multivariate Cox analyses were performed after univariate analyses to identify independent prognostic factors for OS and DFS (Table 3). For male patients, the following factors were identified as independent predictors of OS: CK > 44 IU/L (HR: 0.226, 95% CI: 0.107 to 0.478, P < 0.001), TNM stage (stage II, HR: 2.930, 95% CI: 1.305 to 6.579, P = 0.009; stage III, HR: 3.407, 95% CI: 1.511 to 7.681, P = 0.003), CA199 (HR: 1.001, 95% CI: 1.000 to 1.002, P = 0.003), and postoperative chemotherapy treatment (HR: 0.166, 95% CI: 0.076 to 0.363, P < 0.001). In the multivariate analysis for DFS, CK > 44 IU/L (HR: 0.272, 95% CI: 0.139 to 0.529, P < 0.001), vascular invasion (HR: 2.116, 95% CI: 1.241 to 3.609, P = 0.006), and lymphatic invasion (HR: 1.729, 95% CI: 1.033 to 2.892, P = 0.037) were identified as independent factors.
The relationships between body composition and serum CK in males and females
The sex differences in serum CK concentration and body composition in PC patients were evaluated (Fig. 3). Example images of body composition analysis based on CT are shown in Fig. 3a-d. Males had greater SMA and higher serum CK levels than females; while females had greater areas of SAT. We further analyzed the correlations between CK and various body composition metrics, as shown in Fig. 3. In males, CK levels positively correlated with SMA (r = 0.225, P = 0.025), whereas in females, CK was not correlated with SMA (r = 0.088, P = 0.478). Additionally, in male patients, CK was associated with albumin (r = 0.335, P = 0.001), PNI (r = 0.304, P = 0.002), and BMI (r = 0.228, P = 0.023).
(a-d) Segmentation and measurement of skeletal muscle area at the L3 level based on radiodensity. Muscles highlighted in red comprise the psoas, paraspinal muscles (including erector spinae, multifidus, and quadratus lumborum), and abdominal wall muscles (transversus abdominis, external and internal obliques, and rectus abdominis); (e) Comparisons of body composition and serum CK levels between male and female patients; (f) Correlations between serum CK levels and body composition, albumin concentration, PNI, and BMI. CK, creatine kinase; BMI, body mass index; SMA, skeletal muscle area; SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue; ALB, albumin; PNI, prognostic nutritional index
Discussion
CK is widely distributed in tissues and is generally associated with intracellular energy metabolism, muscle contraction, and ATP regeneration [21]. In the clinical setting, serum CK is a biomarker mainly for identifying myocardial infarction and diseases related to muscle injury. The prognostic value of CK is still under investigation. Several studies concerning the prognostic role of serum CK in other cancers, including hepatocellular cancer [15], esophageal cancer [12], and gastric cancer [13], had indicated low serum CK concentration was a predictor for poor OS and recurrence‑free survival (RFS) in male patients rather than female patients. However, discussion and investigation for mechanisms behind these interesting findings remain insufficient.
Our previous study found that PC could lead to a decrease in serum CK [14]. Considering CK skeletal muscle isoenzyme (CK-MM) is the CK isozyme constituting over 90% of the total serum CK activity [22], which mainly comes from skeletal muscle [23], we believe decreased CK could be the result of muscle wasting due to cancer-related cachexia, as reported by Weber et al. [24] and Takamori et al. [10]. Therefore, serum CK may have a prognostic significance for patients with pancreatic cancer, which is worthy of further investigation. The results of the present study showed a significantly higher incidence of sarcopenia in the low CK group compared to the high CK group in male patients. Additionally, patients in the low CK group had poorer OS and DFS than those in the high CK group. We further investigated the relationship between CK and body composition. We found a significant correlation between CK levels and SMA in male patients, whereas there was no significant relationship in female patients, which explained the absence of association between CK and sarcopenia in female patients.
Two core questions should be addressed before elucidating the mechanisms underlying the prognostic value of CK: (1) Why does CK decreases in cancer patients? (2) why are there sex differences in the prognostic significance of CK? We tried to answer these two questions based on existing evidence, as shown in Fig. 4. Serum CK is predominantly derived from the efflux of CK-MM in muscle fibers [22], and the reason for the decrease in CK should be traced back to the physiopathological changes in skeletal muscle. In cancer patients, both the quality and quantity of skeletal muscle fibers decline, and the decrease of serum CK could possibly be the result of both aspects. Our results show a positive correlation between serum CK and abdominal skeletal muscle area (quantity), although the correlation coefficient was moderate. Considering CK plays a critical role in energy metabolism of muscle fiber, and the association between muscle quality and serum CK levels requires further investigation. In the study by Yen et al. [11], sarcopenia was diagnosed according to a combination of appendicular SMI, skeletal muscle strength, and endurance in subjects without cancer. Similarly, their study found that low serum CK was significantly associated with the occurrence of sarcopenia. Therefore, the decrease in serum CK may be a common phenomenon associated with muscle wasting, and not unique to cancer patients. The explanation that low serum CK related to poor prognosis possibly due to tumor cells consuming serum CK leading to decreased CK, as stated in previous study [15], is doubtful. Sarcopenia in cancer patients does not simply indicate the presence of skeletal muscle wasting but reflects a disturbance of immunonutritional status. In the systemic inflammatory environment triggered by tumors, TNF-α can induce the suppression of myogenic differentiation factor D (MyoD), which is a vital regulator of the synthesis of CK-MM [24,25,26]. Consequently, the efflux of CK-MM may decrease, leading to reduced serum CK activity. Therefore, a decrease in CK levels could be the result of muscle atrophy and the repression of CK-MM expression.
Muscle wasting, serum CK decrease, and sex. In cancer patients, skeletal muscle wasting leads to a decrease in SMA, with a more pronounced reduction in type II muscle fibers compared to type I muscle fibers. Additionally, the synthesis of CK-MM in muscle fibers is inhibited in the inflammatory environment caused by cancer, which further contributes to the reduction of CK-MM efflux from muscle fibers into the bloodstream. Estrogen may be a factor contributing to the lack of prognostic significance of CK in females. CK, creatine kinase; SMA, skeletal muscle area
The limited prognostic effects of CK in females of our study were in accordance with former studies. Serum CK concentration is influenced by race, sex, and age [27], which is similar to the characteristics of skeletal muscle mass [28]. The pathophysiological differences in muscle growth [29], muscle phenotype [30], muscle regeneration [31], and muscle atrophy [32] exist between sexes, and muscle wasting mode also exhibits distinct characteristics in male and female patients [33]. These phenomena suggest that research concerning the prognostic value of skeletal muscle should perform sex-stratified analyses rather than studying males and females as a single group. The study by Yamazaki et al. [13] found the prognostic role of CK in gastric cancer patients; however, further subgroup analysis based on sex did not identify significant prognostic effects in female patients, indicating that the insignificant prognostic effect in females was overshadowed by that of males when evaluating males and females as a whole.
Studies indicating a correlation between CK and SMA did not perform sub-group analyses based on sex [10, 34]. Our sex-stratified analyses found a significant correlation between CK and SMA in male patients and an insignificant correlation in female patients, although the result was significant in the entire cohort (P < 0.001, data not shown in the results). The different primary sex hormones in males and females mediate the sex-specific myogenic processes and responses: testosterone has an anabolic effect that promotes muscle growth, while estrogen may exert its muscle-protective effects through various pathways [35]. There are several explanations for the protective effects of estrogen on muscle [36, 37]: (1) Its structural similarity to potent antioxidants like vitamin E likely confers high antioxidant capacity, limiting oxidative damage; (2) Similar to cholesterol, estrogen can intercalate into membrane phospholipids, providing a stabilizing effect on cell membranes; (3) Estrogen reduces the inflammatory response following muscle damage. Thus, in female patients, the efflux of CK in muscle fibers may decline due to the effect of estrogen, and the correlation between serum CK and skeletal muscle mass is subsequently weakened, which explains the insignificant correlation between the serum CK concentration and SMA in our results. Since most of the female patients in our study were postmenopausal, the effect of menopause on serum CK concentration should be considered. Studies have reported that postmenopausal females had higher baseline CK concentrations [38, 39]. However, a large-scale study showed that CK levels in females were stable with increasing age and were unaffected by menopause [27]. In contrast, males experienced a decline in serum CK concentration with aging [27]. The inconsistent findings, possibly due to small sample sizes and underlying confounding factors, highlight the need for higher-quality studies to fully elucidate how menopause impacts female CK levels.
Moreover, females appear to be inherently less prone to muscle wasting. It was found that estradiol prevented cancer-induced skeletal muscle wasting by reducing the actions of related cytokines such as myostatin, TGF-β, and TNF-α [40]. In pancreatic ductal adenocarcinoma, the abundance of endogenous inhibitors of the activin-family ligands (such as follistatin related protein-1, follistatin like-3, and GASP2/WFIKKN2) protects females from the drivers of muscle wasting, and as a result, males showed earlier and more severe sarcopenia than females [41]. In our cohort, the incidence of sarcopenia in male patients was significantly higher than that in female patients (48.5% vs. 32.8%, P = 0.045). These differences and their connection to the sexual disparity in the prognostic value of CK warrant further investigation.
Body composition is increasingly being valued by oncologists due to the prognostic information it conveys. More attention is now given to individual patient characteristics than ever before, in addition to tumor-specific factors [42]. For patients with resectable PC, the skeletal muscle index assessed by CT images could stratify patients into different prognostic categories [6, 43]. Compounds released from muscles may provide insight into the existence of sarcopenia, serving as a convenient alternative to traditional methods of skeletal muscle mass measurement. For male patients with a low CK level, intensive postoperative follow-up or postoperative adjuvant therapy may be needed. It has been reported that PC patients with decreased skeletal muscle mass have a lower rate of chemotherapy completion compared to those with normal skeletal muscle mass [8], indicating that patients with sarcopenia are more susceptible to the detrimental effects of chemotherapy. The serum CK may provide insight into selecting a chemotherapy regimen and dose intensity as a simple and convenient marker, which requires further investigation to confirm.
In summary, the results of the present study demonstrate the prognostic value of preoperative serum CK in male patients with resectable pancreatic cancer, providing new evidence for the sex dimorphism in CK’s prognostic significance. Additionally, we conducted an in-depth investigation into the association between CK and body composition in cancer patients, offering a possible explanation for the mechanisms underlying the sex dimorphism in CK. There were some limitations to our study. First, due to the retrospective nature of the study, detailed data about CK isozyme levels were not available, which makes it impossible to determine the variation in the CK isozymes. Second, the cutoff values for serum CK were calculated based on subjects from a single institution, the effectiveness of these values requires validation in an external cohort before application in clinic. Third, since CK levels are influenced by race, assessing the prognostic value of CK in different racial groups would be necessary. Additionally, dynamic screening of the CK variation in cancer patients may help to better understand the role CK plays. Hence, further prospective studies are required in the future.
Conclusion
This study demonstrates that serum CK is associated with skeletal muscle mass in male patients with PC. Low preoperative serum CK independently predicts poor survival after curative surgery, a finding that is specific to male PC patients. Preoperative CK may serve as a convenient surrogate marker for traditional measurements of skeletal muscle mass, aiding in clinical decision-making and helping to risk-stratify patients with surgically treated pancreatic cancer. Further prospective studies are needed to confirm the utility of this convenient prognostic marker.
Data availability
The datasets used and analyzed during the current study available from the corresponding author on reasonable request.
Abbreviations
- BMI:
-
Body mass index
- CI:
-
Confidence interval
- CK:
-
Creatine kinase
- DFS:
-
Disease-free survival
- EWGSOP:
-
European Working Group on Sarcopenia in Older People
- GC:
-
Gastric cancer
- HR:
-
Hazard ratio
- HU:
-
Hounsfield unit
- MyoD:
-
Myogenic differentiation factor D
- OR:
-
Odds ratio
- OS:
-
Overall survival
- PACS:
-
Picture archiving and communication system
- PC:
-
Pancreatic cancer
- PDAC:
-
Pancreatic ductal adenocarcinoma
- PNI:
-
Prognostic nutritional index
- SAT:
-
Subcutaneous adipose tissue
- SMA:
-
Skeletal muscle area
- SMI:
-
Skeletal muscle index
- VAT:
-
Visceral adipose tissue
- TGF:
-
Transforming growth factor
- TNF:
-
Tumor necrosis factor
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Acknowledgements
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Authors and Affiliations
Contributions
Conceptualization: CC, XL, FL; Methodology: XCL, RL, YY; Data curation: HF; Formal analysis: CC, XL, TT; Supervision: HH, FL; Writing – original draft: CC, XL; Writing – review & editing: All authors.
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Ethics approval and consent to participate
This study was approved by the Ethics Committee of Fujian Medical University Union Hospital (Approval No.2023KY080). Informed consent was obtained from all individual participants included in the study. All methods of this study were carried out in accordance with relevant guidelines and regulations.
Foundation
This work was supported by the National Natural Science Foundation of China (Grant No.: 82073139), the Natural Science Foundation of Fujian Province, China (No. 2020J02054), the Joint Funds for the Innovation of Science and Technology, Fujian Province (Grant number: 2021Y9058) and the Medical Minimally Invasive Center Program of Fujian Province and National Key Clinical Specialty Discipline Construction Program, China.
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Not applicable.
Competing interests
The authors declare no competing interests.
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Cong Chen and Xin Luo share first authorship.
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Chen, C., Luo, X., Lin, X. et al. An exploratory study of serum creatine kinase as a prognostic marker for patients with resectable pancreatic cancer: looking into the relationship with body composition. Nutr J 24, 22 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12937-025-01084-x
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DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12937-025-01084-x