Abstract
Background/Aim: Accumulating evidence suggests that muscle mass depletion (sarcopenia) has a negative impact on survival in several malignancies, including biliary tract cancer (BTC). Computed tomography (CT)-measured psoas muscle thickness to height ratio (PMTH) has been reported as a surrogate measure for muscle mass that does not require specialized equipment or software. The aim of this retrospective study was to investigate whether preoperative PMTH predicts oncological outcomes of patients undergoing surgical resection for BTC. Patients and Methods: PMTH was assessed in 211 patients by analyzing axial CT images at the level of the umbilicus. The most predictive cutoff of PMTH was determined by survival classification and regression tree analysis. Propensity score-based inverse probability weighting (IPW) was used to balance characteristics between the low and high PMTH groups. Results: Applying a PMTH cutoff of 17.5 mm/m, the low PMTH group comprised 114 patients (54%). Low PMTH was associated with female sex, non-obesity, CA19-9 elevation, and lymph node metastasis. After IPW adjustment, the low PMTH group had a significantly shorter disease-specific survival (p<0.001) and relapse-free survival (p<0.001) than the high PMTH group. IPW-adjusted regression analysis revealed that a low PMTH was independently associated with worse disease-specific survival (hazard ratio=2.98, p<0.001) and relapse-free survival (hazard ratio=2.49, p<0.001), in addition to other factors such as tumor differentiation, perineural invasion, and resection margin status. Conclusion: Preoperative PMTH may be a simple and feasible index of sarcopenia for predicting poor survival after resection of BTC.
Biliary tract cancer (BTC) is an aggressive malignancy arising from the intra- or extrahepatic bile ducts, the gallbladder, and the ampulla of Vater. The incidence of BTC is relatively high in the Asia-Pacific region and continues to increase worldwide (1). Complete surgical resection with negative margin represents the only curative option; however, the 5-year overall survival rate is only approximately 25-50% (2, 3). Studies have reported ways to improve BTC treatment including early diagnosis, advanced surgical techniques, and chemotherapy (3, 4).
Oncological outcomes of patients with cancer can also be influenced by patient-related factors such as body composition and functional status. Many studies have reported that alteration of body composition, in particular muscle mass depletion, induces sarcopenia that may negatively impact survival in various malignancies, including BTC (5-10). However, sarcopenia remains under-recognized in routine clinical practice, partly due to a lack of easily accessible diagnostic tools. Most diagnostic criteria for sarcopenia recommend the use of specialized equipment, such as dual-energy X-ray absorptiometry and bioelectrical impedance analysis, for measuring skeletal muscle mass index (SMI, kg/m2) (11, 12). Computed tomography (CT) has been widely used for measuring muscle mass and the ratio of the total area of skeletal muscles at the level of the third lumbar vertebra to height squared is often used for calculating the SMI (6-8). However, this method usually requires specific imaging software and is difficult to generalize for clinical practice.
CT-measured transversal psoas muscle thickness (PMT) to height ratio (PMTH) has recently emerged as an easily measurable surrogate for muscle mass, as it requires no use of additional tools (13). PMTH has been reported to be effective for detecting sarcopenia as well as for predicting mortality in patients with cirrhosis (13-19). However, there have been few studies of the prognostic value of PMTH in patients with cancer to date.
In the present study, we aimed to explore whether preoperative PMTH can predict oncological outcomes in patients with BTC undergoing surgical resection.
Patients and Methods
Patients, data collection and ethics statement. A total of 248 consecutive patients with histologically proven BTC who underwent surgical resection at our Institute between January 2010 and May 2022 were retrospectively identified. Of these, patients undergoing surgery with palliative intent (n=23), those with incomplete clinicopathological data (n=9), and those without abdominal CT taken within 1 month before surgery (n=5) were excluded; 211 patients were finally enrolled. The primary tumor sites were as follows: intrahepatic bile duct in 42, extrahepatic bile duct in 108, gallbladder in 30, and the ampulla of Vater in 31 cases. One hundred and thirty-two (63%) patients who had biliary obstruction underwent biliary stenting as a bridge to surgery. All patients had serum carbohydrate antigen 19-9 (CA19-9) levels preoperatively (after biliary stenting/drainage and within 1 month before surgery) determined using a chemiluminescent enzyme immunoassay kit (Fujirebio, Tokyo, Japan). Histopathological parameters included tumor node metastasis (TNM) stage according to the seventh edition of the Union for International Cancer Control TNM system (20), tumor differentiation, perineural invasion, and status of resection margin. Resection margins were classified as follows: R0, no residual tumor; R1, microscopic residual tumor; and R2, macroscopic residual tumor. Ten patients who did not undergo lymphadenectomy (consisting of transduodenal ampullectomy for ampullary cancer in seven and cholecystectomy for gallbladder cancer in three) were categorized as N0. Fifteen out of 211 patients (7.1%) were found to have limited metastatic disease during surgical exploration (para-aortic lymph nodes in six, liver in six, and peritoneum in three), but these patients underwent simultaneous resection of primary and metastatic lesions. The median follow-up time was estimated using the reverse Kaplan–Meier method (21). Disease-specific survival (DSS) was calculated from the date of surgery to the date of last follow-up or BTC-related death. Relapse-free survival (RFS) was defined from the date of surgery to the date of finding local, regional or distant recurrence. This study was approved by the Institutional Ethics Committee of Meiwa Hospital (approval no.: 2022-36) as a retrospective analysis of the collected data in accordance with the ethical standards of the World Medical Association’s Declaration of Helsinki. Individual consent for this retrospective analysis was waived.
Measurement of PMTH. Using abdominal CT performed with a multidetector-row scanner (Brilliance-iCT, Philips Medical Systems, Cleveland, OH, USA) with scan parameters of 120 kVp/200 mAs, 128×0.625-mm slice collimation, and 512×512 pixels, axial plain images at the level of the umbilicus were analyzed using a picture archiving and communication system (ShadeQuest/ViewR V1.22.81; Yokogawa Medical Solutions, Tokyo, Japan) for PMT measurement. Transversal PMT was defined as the diameter of the right psoas muscle perpendicular to the axial diameter, as reported previously (13-19). PMT (mm) was then divided by the patient’s height (m) to obtain PMTH (mm/m).
Statistics. For between-group comparisons, either the chi-square test or Fisher’s exact test was used for categorical variables. The most predictive cutoff value for dividing patients into groups with low or high PMTH was determined by survival classification and regression tree (CART) analysis. To adjust for patient characteristics, the two groups were balanced by propensity score-based inverse probability weighting (IPW). The propensity score was calculated for each patient using a logistic regression model that included all of the assessed variables. Covariate balance was checked before and after IPW using standardized differences (SD) and groups were considered balanced when the SDs of all covariates were less than 0.1. IPW-adjusted Kaplan–Meier analysis with a log-rank test was used to compare DSS and RFS of the low versus high PMTH groups. IPW-adjusted Cox regression analyses were performed to identify independent predictors of DSS and RFS, and for subgroup analysis. All statistical analyses were conducted using R 4.2.2 software (Foundation for Statistical Computing, Vienna, Austria) and p<0.05 was considered significant.
Results
Baseline characteristics. The study population consisted of 116 males and 95 females with a median age of 72 years (range=39-88 years). Survival CART analysis provided a prognostic cutoff of PMTH at 17.5 (mm/m). Overall, 114 (54%) patients were stratified into a low PMTH (≤17.5 mm/m) group and 97 (46%) into a high PMTH group. The low PMTH group had more females, fewer obese individuals (body mass index ≥25 kg/m2), and higher frequencies of patients with CA19-9 elevation and lymph node metastases, as shown in Table I. After application of IPW, the characteristics of interest were well balanced, with an SD of less than 0.1.
Baseline patient characteristics.
Association between PMTH and DSS. The median follow-up for the weighted population was 66.6 months, with a 95% confidence interval (CI) of 54.4-83.1 months. Adjusted Kaplan–Meier analysis showed that the low PMTH group had a significantly shorter DSS than the high PMTH group [median=26.6 (95% CI=21.0-44.3) months vs. not reached (95% CI=50.9 months-not available); p<0.001] (Figure 1A). Adjusted Cox regression revealed that a low PMTH was an independent factor for poor DSS by multivariate analysis (hazard ratio=2.98, 95% CI=1.85-4.80; p<0.001). Furthermore, extrahepatic cholangiocarcinoma (vs. ampulla of Vater cancer), moderate/poor tumor differentiation, perineural invasion, and R1/R2 resection margin status were independent prognostic factors for poorer DSS (Table II).
Inverse probability weighting-adjusted Kaplan–Meier survival curves. A comparison of disease-specific (A) and relapse-free (B) survival between groups with low and high psoas muscle thickness to height ratio (PMTH).
Inverse probability weighting-adjusted univariate and multivariate analyses of prognostic factors.
Association between PMTH and RFS. Similarly to DSS, the difference in RFS between the low and high PMTH groups in the weighted population was statistically significant by adjusted Kaplan-Meier analysis [median=13.3 (95% CI=9.4-18.9) months vs. 46.9 months (95% CI=19.9 months-not available); p<0.001] (Figure 1B). Adjusted Cox regression revealed that a low PMTH was an independent factor for poor RFS (hazard ratio=2.49, 95% CI=1.60-3.87; p<0.001), in addition to other factors (higher N or M stage, moderate/poor tumor differentiation, perineural invasion, and R1/R2 resection margin) (Table II).
Subgroup analysis. Subgroup analysis of DSS and RFS according to baseline characteristics was performed using adjusted Cox regression to further explore the association between PMTH and patients’ survival. As shown in Figure 2, a low PMTH tended to be consistently associated with worse DSS and RFS. Associations in several subgroups were observed, especially for a low PMTH and RFS; however, these were not significant.
Forest plot of subgroup analysis for disease-specific (A) and relapse-free (B) survival. ASA-PS: American Society of Anesthesiologists physical status; BMI: body mass index; CA19-9: carbohydrate antigen 19-9; CI: confidence interval; HR: hazard ratio; mod: moderately differentiated adenocarcinoma; PMTH: psoas muscle thickness per height; por: poorly differentiated adenocarcinoma; well: well-differentiated adenocarcinoma.
Discussion
In the present study, a low preoperative CT-measured PMTH was associated with poor DSS and RFS independently of well-known prognosticators, such as lymph node metastases, perineural invasion, and radicality of surgery (22, 23), suggesting that PMTH provides valuable prognostic information preoperatively. Our findings are consistent with previous studies that showed poor survival outcomes in patients with BTC with sarcopenia, although cancer type, treatment setting and method of measuring muscle mass varied among the studies (8-10). A recent review by Watanabe et al. reported on 13 studies using SMI, seven studies using psoas muscle index, four studies using skeletal muscle area, and five studies using other indices, for defining sarcopenia in patients with BTC (10). To our knowledge, our study is the first to analyze PMTH and its association with survival in patients undergoing surgical resection for BTC.
Previous work measuring PMTH for defining sarcopenia have mostly been limited to studies on patients with cirrhosis (13-19). Some of these studies mentioned the potential advantage of using PMTH, as dual-energy X-ray absorptiometry and bioelectrical impedance analysis are sensitive to hydration status; thus, they may not be suitable for patients with cirrhosis. As abdominal CT is routinely ordered for preoperative staging in patients with BTC, its use for sarcopenia evaluation will not require additional cost or radiation exposure. Moreover, since PMTH is based only on the psoas muscle diameter, it is readily available compared to conventional CT cross-sectional indices such as SMI. A study by Kim et al. conducted on 65 patients with cirrhosis with ascites showed that the prognostic performance of PMTH (≤14 mm/m) for predicting 1-year mortality was higher than that of Child–Pugh score, Model for End-stage Liver Disease (MELD) score, and serum sodium to MELD score (14). In a study of 653 patients with cirrhosis, Gu et al. reported a significant correlation between PMTH and SMI (correlation coefficient=0.526, p<0.001), suggesting that PMTH is a good substitute for SMI (15). Interestingly, Paternostro et al. reported that PMTH was independently associated with mortality in patients with cirrhosis, but SMI was not (17). The reason was unclear but they concluded that PMTH outperformed SMI despite requiring less infrastructure and resources to obtain.
The pathophysiology of sarcopenia and how it leads to increased risk of mortality among patients with cancer is complicated. Multiple studies have proposed that not only normal aging but also cancer-induced systemic inflammation, malnutrition, autophagy and physical inactivity promote muscle wasting and weakness (24, 25). These changes involve catabolic pathways that are mediated by humoral factors, such as pro-inflammatory cytokines, and are exacerbated as cancer progresses, resulting in poor prognosis. Interleukin-6 and tumor necrosis factor-α, which are involved in crosstalk between cholangiocarcinoma and neighboring cells, play important roles in stimulating muscle proteolysis and myocyte apoptosis (26), as well as in supporting cancer cell proliferation, survival, and metastatic dissemination (27). Moreover, sarcopenia is associated with postoperative complications (10), increased chemotherapy toxicity (7), and shorter time to treatment failure (9), factors that may also lead to shorter survival. Theoretically, strategies to improve muscle wasting may have therapeutic implications in cancer treatment. In the IMPACT study by Basile et al., early loss of more than 10% of skeletal muscle mass during chemotherapy had a negative prognostic role in patients with advanced pancreatic cancer, but nutritional support or intervention did not impact prognosis in terms of overall survival (28). Selumetinib, an inhibitor of mitogen-activated protein/extracellular signal-regulated kinase and of interleukin-6 secretion, has been shown to increase muscle mass in patients with cholangiocarcinoma; however, a survival benefit was not evident (29). The impact of therapeutic interventions for sarcopenia on cancer survival remain uncertain and further studies are needed to confirm clinical efficacy.
There were several limitations of this study. Firstly, it was a retrospective, single-center study with a relatively small sample size. Secondly, only preoperative PMTH data were used for the analysis; longitudinal changes of PMTH during the follow-up period were not considered. Thirdly, PMTH was measured by only one examiner to prevent inter-observer measurement bias. However, a previous study reported that measurement of PMTH yielded a good intraclass correlation coefficient of 0.906 between two observers (14). Fourthly, PMTH does not reflect muscle quality. Previous studies reported that a decline of muscle quality characterized by fatty infiltration of muscle reduces overall survival of patients with BTC (8, 10); however, a methodology for assessing muscle quality has not yet been standardized. Finally, we determined only one cutoff value for PMTH in both males and females. Many previous studies have used sex-specific cutoff values to define sarcopenia using different muscle mass indices. In this study, a low PMTH was more common in females. However, our subgroup analysis revealed a significant association between low PMTH and worse DSS for both sexes. The cutoff value for defining sarcopenia in individual studies may also vary depending on factors such as disease, race, sample size, study endpoint, and statistical method. Additional studies are needed to determine a more robust cutoff for PMTH.
In conclusion, PMTH may be a simple and highly feasible index for evaluating muscle mass depletion in a daily clinical setting. This study suggests evaluation of preoperative PMTH aids in predicting poor survival after resection of BTC. Further studies are needed to establish a more tractable method for diagnosing sarcopenia among patients with cancer.
Acknowledgements
The Authors would like to thank all the patients and medical staff at the Institution who contributed to this study.
Footnotes
Authors’ Contributions
All the Authors have contributed significantly to the concept design of this study and article, leading to the final version. All Authors have reviewed the article and agreed with its content.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
- Received January 25, 2023.
- Revision received February 9, 2023.
- Accepted February 10, 2023.
- Copyright © 2023 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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