Akazawa Y, Ohtani M, Murata Y, Tanaka T, Nosaka T, Takahashi K, Naito T, Nakamoto Y. Three-dimensional psoas muscle volume and longitudinal changes as predictors of outcomes in older patients with advanced pancreatic cancer. World J Gastroenterol 2026; 32(24): 118757 [DOI: 10.3748/wjg.118757]
Corresponding Author of This Article
Yasunari Nakamoto, MD, PhD, Professor, Department of Gastroenterology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-Cho, Yoshida-Gun, Fukui 910-1193, Japan. nakamoto-med2@med.u-fukui.ac.jp
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Akazawa Y, Ohtani M, Murata Y, Tanaka T, Nosaka T, Takahashi K, Naito T, Nakamoto Y. Three-dimensional psoas muscle volume and longitudinal changes as predictors of outcomes in older patients with advanced pancreatic cancer. World J Gastroenterol 2026; 32(24): 118757 [DOI: 10.3748/wjg.118757]
Yu Akazawa, Masahiro Ohtani, Yosuke Murata, Tomoko Tanaka, Takuto Nosaka, Kazuto Takahashi, Tatsushi Naito, Yasunari Nakamoto, Department of Gastroenterology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
Author contributions: Akazawa Y, Ohtani M, and Nakamoto Y designed this study; Akazawa Y collected all the data and wrote the manuscript; Akazawa Y and Ohtani M analyzed the data; all authors critically reviewed and provided final approval of the manuscript, and were responsible for the decision to submit the manuscript for publication.
Supported by Japan Society for the Promotion of Science KAKENHI Grant-in-Aid for Scientific Research, No. 25K19290.
Institutional review board statement: This study was approved by the Institutional Review Board of the University of Fukui, No. 20220008.
Informed consent statement: The Ethics Committee waived the need for written informed consent for this retrospective study.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
Corresponding author: Yasunari Nakamoto, MD, PhD, Professor, Department of Gastroenterology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-Cho, Yoshida-Gun, Fukui 910-1193, Japan. nakamoto-med2@med.u-fukui.ac.jp
Received: January 12, 2026 Revised: February 17, 2026 Accepted: March 23, 2026 Published online: June 28, 2026 Processing time: 153 Days and 19.6 Hours
Abstract
BACKGROUND
Pancreatic cancer (PC) has one of the poorest prognoses among malignant diseases worldwide. In chemotherapy for advanced PC, the anti-tumor effect and tolerability often vary among patients, and reliable biomarkers to predict these outcomes remain unclear. Sarcopenia is recognized as an important prognostic factor in various cancers, and three-dimensional (3D) skeletal muscle volumetric analysis has recently emerged as an objective method for evaluating muscle status. However, the clinical and prognostic implications of volumetric skeletal muscle assessment in older patients with advanced PC undergoing gemcitabine plus nab-paclitaxel therapy have not been fully clarified.
AIM
To clarify the usefulness of 3D muscle volumetric analysis in predicting tolerability and prognosis in older patients with advanced PC.
METHODS
We retrospectively enrolled 150 older patients (aged ≥ 65 years) with unresectable PC, including those with locally advanced and/or metastatic disease, who received first-line gemcitabine plus nab-paclitaxel therapy and evaluated the impact of sarcopenia on time to treatment failure (TTF), overall survival (OS), and progression-free survival (PFS). Psoas muscle volume was semi-automatically measured using a 3D image analysis system, and sarcopenia was defined by sex-specific psoas volume index cut-offs. Additionally, longitudinal muscle changes at baseline and two months after treatment initiation were evaluated to determine their prognostic relevance.
RESULTS
Forty-six (30.7%) patients were diagnosed with sarcopenia; the median TTF was significantly shorter in sarcopenic patients (59 days vs 211 days; P < 0.001). OS and PFS were also significantly worse in sarcopenic patients (median OS: 175 days vs 562 days, P < 0.001; median PFS: 88 days vs 242 days, P < 0.001). Multivariate analysis identified sarcopenia as an independent prognostic factor for poor TTF, OS, and PFS (all P < 0.001). Severe adverse events (> grade 3) occurred more frequently in patients with sarcopenia than in those without (47.8% vs 26.9%; P = 0.015). Among 135 patients with sequential imaging, the non-sarcopenia-maintenance group (n = 72) showed significantly longer OS (median 615 days) than the sarcopenia-progression (n = 25; 205 days) and sarcopenia-maintenance groups (n = 35; 185 days; P < 0.001).
CONCLUSION
Sarcopenia defined by 3D psoas volume index and early muscle deterioration were strongly associated with poor tolerability and survival, indicating that volumetric assessment may predict outcomes in older patients with advanced PC.
Core Tip: Sarcopenia is increasingly recognized as a key determinant of survival outcomes in various cancers. In this study, a three-dimensional psoas volume index was used to evaluate skeletal muscle dynamics in relation to clinical outcomes in older patients with advanced pancreatic cancer undergoing gemcitabine plus nab-paclitaxel therapy. Baseline sarcopenia and early muscle deterioration were strongly associated with poor tolerability, shorter time to treatment failure, and markedly reduced survival. These findings highlight that volumetric skeletal muscle assessment before and during chemotherapy may help predict clinical outcomes and contribute to more individualized treatment optimization in older patients with pancreatic cancer.
Citation: Akazawa Y, Ohtani M, Murata Y, Tanaka T, Nosaka T, Takahashi K, Naito T, Nakamoto Y. Three-dimensional psoas muscle volume and longitudinal changes as predictors of outcomes in older patients with advanced pancreatic cancer. World J Gastroenterol 2026; 32(24): 118757
Pancreatic cancer (PC) has one of the worst prognoses of any malignant disease worldwide, with a five-year survival rate of approximately 10%[1-3]. Most patients with PC are diagnosed at a late stage, including locally advanced or metastatic cancers, and are treated with chemotherapy[4,5]. Gemcitabine plus nab-paclitaxel (GnP) therapy has been established as one of first-line chemotherapy regimens for patients with unresectable locally advanced or metastatic PC[6]. In addition, GnP therapy is characterized by milder adverse events compared with FOLFIRINOX, another standard chemotherapy; therefore, it tends to be a suitable drug and can be frequently used in older patients with PC[7]. Owing to its widespread use and relatively favorable tolerability profile in older patients, identifying predictors of treatment response and toxicity in patients receiving GnP therapy is of particular clinical importance. However, in most chemotherapy regimens, even with the same dose and relative dose intensity (RDI), tolerability and therapeutic effects often vary between patients. This finding would be no exception in GnP therapy for PC. In fact, some patients with PC who received GnP therapy had good tolerance and dramatic anti-tumor effects, with improved survival, whereas others experienced severe adverse events and tumor growth. Furthermore, in older patients, adverse events of chemotherapy may lead to a poor quality of life and could sometimes directly result in death. Therefore, to maximize the expected anti-tumor effect of chemotherapy and determine effective treatment strategies, it is essential to identify useful predictors of tolerability and clinical outcomes in patients with PC receiving GnP therapy, especially older patients.
Recently, it has been established that sarcopenia, defined as a morbid status involving loss of skeletal muscle mass and physical function, could be closely involved in the clinical outcome of various diseases[8-10]. In the field of malignant diseases, meta-analyses have demonstrated that sarcopenia is an independent poor prognostic factor and contribute to increased chemotherapy toxicity[11-13]. Similarly, in PC, sarcopenia has been reported to be closely associated with poor treatment response and poor prognosis[14-17]. On the other hand, another study found that sarcopenia was not a prognostic predictor in patients with advanced PC who received chemotherapy[18]. This inconsistency may be due to differences in the measurement methods for skeletal muscles and to the heterogeneity of sarcopenia criteria. Therefore, the effect of sarcopenia on the tolerability and clinical prognosis of patients with advanced PC undergoing chemotherapy remains unclear.
Two-dimensional (2D) cross-sectional analysis methods, including the psoas area index of the bilateral psoas muscle areas at the third lumbar vertebra (L3) level using computed tomography (CT) and magnetic resonance imaging, have been widely used to measure skeletal muscle mass for the evaluation of sarcopenia[17-21]. However, muscle mass parameters derived from 2D cross-sectional images reflect only a limited range of muscle areas, potentially leading to inaccurate sarcopenia diagnosis. In recent years, quantitative analysis of skeletal muscles using three-dimensional (3D) volumetric imaging systems has attracted attention as a novel method for measuring muscle mass. Wide 3D volumetric parameters reflect a patient’s whole-body composition more accurately than narrow 2D image parameters[22]. In addition, previous reports have shown that sarcopenia based on skeletal muscle volume may be associated with the prognosis and respiratory complications in patients with non-small-cell lung cancer[23,24]. However, to the best of our knowledge, few studies have investigated the impact of muscle parameter dynamics obtained from 3D volumetric images on the therapeutic effects of chemotherapy in advanced PC. Therefore, this study aimed to clarify the usefulness of quantitative longitudinal analysis of skeletal muscle using a 3D imaging system as a predictor of tolerability and prognosis in older patients with PC who received first-line GnP therapy.
MATERIALS AND METHODS
Patients and follow-up
We retrospectively analyzed consecutive older patients with unresectable PC, including those with locally advanced or metastatic disease, who initiated GnP therapy as a first-line chemotherapy regimen between July 2015 and September 2025 at our institution. In this study, older individuals were defined as those aged > 65 years, in accordance with the World Health Organization classification. All enrolled patients were pathologically diagnosed with pancreatic ductal adenocarcinoma using endoscopic ultrasound-guided fine-needle biopsy or endoscopic retrograde cholangiopancreatography. Patients who were lost to follow-up within 30 days of starting GnP chemotherapy were excluded. In addition, all enrolled patients were evaluated for pretreatment clinical staging, tumor local extension, and metastasis using contrast-enhanced CT, endoscopic ultrasound, fluorodeoxyglucose-positron emission tomography, and/or magnetic resonance imaging before GnP chemotherapy. Eligible patients were divided according to the presence or absence of sarcopenia using a 3D imaging system. During GnP chemotherapy, patients were carefully followed up after the initial treatment with physical examinations and blood tests every 1-2 weeks, and chest and abdominal CT scans every 6-10 weeks. Follow-up data were confirmed until December 1, 2025, or the time of death. This study was approved by the Institutional Review Board of the University of Fukui, No. 20220008 and was conducted in accordance with the principles of the Declaration of Helsinki. The ethics committee waived the requirement for written informed consent for this retrospective study. Furthermore, because this was a retrospective study that enrolled all consecutive eligible patients managed during the study period, no formal sample size or power calculation was conducted prior to data collection.
Chemotherapy treatment
All enrolled patients received an intravenous infusion of gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8, and 15 at four-week intervals as GnP chemotherapy. Gemcitabine and nab-paclitaxel dose modifications were performed depending on the patient’s general condition, laboratory data, and adverse events. The RDI of gemcitabine and nab-paclitaxel was defined as the ratio of the actual dose intensity to the standard dose intensity in the first two treatment cycles. GnP chemotherapy was continued until disease progression or unacceptable adverse events. Patients with progressive disease were offered either a second-line chemotherapy regimen or the best supportive care.
Data collection
The following clinical and oncological data of the enrolled patients were extracted from their electronic medical records: Age, sex, weight, body mass index, Eastern Cooperative Oncology Group Performance Status (ECOG PS), tumor size on CT imaging, tumor location (pancreatic head or body and tail), clinical stage of cancer (locally advanced or metastatic), and blood examination results [leukocyte, neutrophil, lymphocyte, platelet, albumin, C-reactive protein (CRP), carbohydrate antigen 19-9 (CA19-9), total cholesterol, and cholinesterase levels]. In addition, the following nutritional- and inflammatory-based scores were determined from blood examinations: Neutrophil-to-lymphocyte ratio (NLR), modified Glasgow Prognostic Score (m-GPS = 0 was defined as CRP ≤ 1.0, albumin > 3.5, m-GPS = 1 was defined as CRP > 1.0 or albumin < 3.5, m-GPS = 2 was defined as CRP > 1.0 or albumin < 3.5), and prognostic nutritional index (PNI) (calculated as 10 × albumin + 0.005 × lymphocyte).
Endpoint
The primary endpoints of this study were time to treatment failure (TTF), defined as the time from the start of GnP chemotherapy to discontinuation for any cause, overall survival (OS), and progression-free survival (PFS) in the sarcopenic and non-sarcopenic groups. OS was calculated from the date of the first administration of GnP chemotherapy to the date of death from any cause, and PFS was calculated from the date of the first administration of GnP chemotherapy to the date of radiological disease progression or death. Patients who survived without disease progression at the end of the study period were censored as the time of last follow up. The secondary endpoints were clinical tumor response and adverse events for GnP chemotherapy in the sarcopenic and non-sarcopenic groups. Tumor response was evaluated by contrast-enhanced CT according to the Response Evaluation Criteria in Solid Tumors version 1.1, as follows: Complete response, partial response, stable disease, and progressive disease. Adverse events were graded according to the Common Terminology Criteria for Adverse Events version 5.0. Further, RDI was assessed throughout the first two cycles to reflect the initial treatment intensity and tolerability, thus minimizing the influence of disease progression or treatment discontinuation in later cycles.
Image analysis of skeletal muscle volume
All abdominopelvic CT images were obtained within 4 weeks prior to chemotherapy, and the skeletal muscle volume was assessed by measuring the total bilateral psoas muscle volume (PMV) (Figure 1). All images were analyzed using the Ziostation 2 software (Ziosoft, Tokyo, Japan). PMV measurements were performed using an automated analysis program installed on a workstation. In addition, the displacement of the muscle region used to calculate the segmentation error was manually modified. The total PMV (cm3) for each patient was divided by the cube of the height (m3) to produce normalized PMV values, which were defined as the psoas volume index (PVI) (cm3/m3). Also, based on a previous report, the optimal cutoff values for PVI were determined as 61.5 cm3/m3 for men and 44.1 cm3/m3 for women[25]. Sarcopenia was defined as a PVI below the sex-specific cutoff values, set at < 61.5 cm³/m³ for men and < 44.1 cm³/m³ for women. Further, sarcopenia progression was defined as a change from non-sarcopenic status at baseline to sarcopenic status at two months based on the sex-specific PVI cutoffs. All imaging assessments were performed by one expert gastroenterologist and confirmed and agreed upon by two other expert gastroenterologists.
Figure 1 Psoas muscle mass analysis by three-dimensional imaging using pre-chemotherapy computed tomography in sarcopenic and non-sarcopenic patients.
A-C: In a representative non-sarcopenic patient, bilateral psoas muscle areas (red) at the third lumbar vertebra level on axial computed tomography (CT) (A) and at the maximum level on coronal CT (B), and bilateral psoas muscle volume extracted by semi-automatic image analysis (C); D-F: In a representative sarcopenic patient, bilateral psoas muscle areas (red) at the third lumbar vertebra level with axial CT image (D) and at the maximum level with coronal CT image (E), and bilateral psoas muscle volume extracted by semi-automatic image analysis (F).
Statistical analysis
All statistical analyses were performed using R version 4.5.2 (R Foundation for Statistical Computing, Vienna, Austria). Categorical variables were expressed as n (%) and compared using Fisher’s exact test. Continuous variables are described as medians and ranges and were compared using the Mann-Whitney U test. TTF, PFS, and OS were estimated using the Kaplan-Meier method, and differences between the curves were evaluated using the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards model to identify variables significantly associated with tolerability and prognosis, and odds ratios and 95% confidence intervals (CIs) were calculated. Multivariate analysis of the significant factors (P < 0.05) from the univariate analysis was performed to identify independent factors associated with TTF, PFS, and OS. To avoid multicollinearity, inflammatory and nutritional variables derived from overlapping components (e.g., m-GPS, CRP, albumin, NLR, neutrophil count, lymphocyte count, and PNI) were not entered simultaneously into the same multivariate model. Further, the m-GPS (0 vs 1-2) was used as the representative inflammatory/nutritional index in the primary TTF model, while sensitivity analyses were conducted by replacing m-GPS with PNI or NLR in separate multivariate models. P values < 0.05 were considered to indicate a statistically significant difference.
RESULTS
Baseline characteristics
Between July 2015 and September 2025, 159 older patients (> 65 years) with unresectable PC underwent first-line GnP chemotherapy at the University of Fukui Hospital. Of these, nine patients were excluded because they did not undergo follow-up for more than 30 days after GnP administration. Finally, 150 patients were enrolled in the study.
There were 70 females (46.7%) and 80 males (53.3%) with a median age of 72.1 years (range: 65-85 years). The median observation period was 268.5 days (range: 31-1665 days). In addition, among enrolled patients, the sarcopenic and non-sarcopenic groups, as determined by PVI calculated using 3D volumetric imaging systems, included 46 (30.7%) and 104 (69.3%) patients, respectively. A comparison of the baseline clinical characteristics between the sarcopenic and non-sarcopenic groups is shown in Table 1. There were no significant differences in age or sex between the groups. The sarcopenic group had a significantly lower weight (P = 0.003), lower body mass index (P < 0.001), and poor ECOG PS (P = 0.043) than the non-sarcopenic group. Also, the median PVI of the sarcopenic group were 56.4 cm3/m3 for men and 40.1 cm3/m3 for women, compared with 82.2 cm3/m3 for men and 63.4 cm3/m3 for women in the non-sarcopenic group (P < 0.001). No significant differences in tumor size or location were observed between the two groups. In addition, at the clinical stage, the sarcopenic group had a higher proportion of patients with metastasis than the non-sarcopenic group (P = 0.015). There were no differences between the two groups in terms of blood examination and nutritional- and inflammation-based scores, including leukocytes, neutrophils, lymphocytes, platelets, albumin, CRP, total cholesterol, NLR, mGPS, and PNI. In contrast, significant differences were observed between the two groups in CA19-9 and cholinesterase levels (P = 0.040 and P = 0.009, respectively).
Table 1 Baseline characteristics of enrolled patients, median (range)/n (%).
The completion rates of GnP until one and two cycles in the sarcopenic group were significantly lower than those in the non-sarcopenic group (P < 0.001; Table 2). In the sarcopenic group, the completion rates of GnP until one and two cycles were 65.2% and 51.2%, respectively, whereas in the non-sarcopenic group, the completion rates of GnP until one and two cycles were 98.0% and 94.1%, respectively. The TTF of patients in the sarcopenic and non-sarcopenic groups are shown in Figure 2. The median TTF for the sarcopenic and non-sarcopenic groups were 59 days and 211 days, respectively, and patients in the sarcopenic group had a significantly shorter TTF than those in the non-sarcopenic group (P < 0.001). The univariate and multivariate analyses of TTF using the Cox proportional hazards model are shown in Tables 3 and 4. On univariate analysis, head in location of tumor (P = 0.040), metastasis in clinical stage (P < 0.001), high CRP (P = 0.008), high CA19-9 (P = 0.002), low cholinesterase (P = 0.011), high NLR (P = 0.018), high m-GPS (P = 0.003), low PNI (P = 0.011), and sarcopenia (P < 0.001) were significantly associated with poor TTF. To avoid any multicollinearity among overlapping inflammatory and nutritional parameters, m-GPS was selected as the representative index in the primary multivariate model. Multivariate analysis revealed that sarcopenia [hazard ratio (HR) = 4.75; 95%CI: 2.96-7.62, P < 0.001] and metastasis in the clinical stage (HR = 1.63; 95%CI: 1.02-2.60, P = 0.039) were independent significant clinical factors predicting poor TTF in older patients with unresectable PC receiving GnP therapy as first-line chemotherapy. Furthermore, sarcopenia remained an independent prognostic factor for TTF even in sensitivity analyses replacing m-GPS with PNI or NLR (Supplementary Tables 1 and 2).
Figure 2 Kaplan-Meier curves for time to treatment failure in enrolled patients with and without sarcopenia.
The time to treatment failure of the sarcopenic group (dotted blue line) was significantly shorter than that of the non-sarcopenic group (solid orange line) (P < 0.001, log-rank test). The median time to treatment failure in the sarcopenic and non-sarcopenic groups were 59 and 211 days, respectively.
Table 2 Treatment efficacy and treatment course in the sarcopenic and non-sarcopenic patients, median (range)/n (%).
A comparison of the treatment response to GnP chemotherapy and the RDIs of gemcitabine and nab-paclitaxel between the sarcopenic and non-sarcopenic groups is shown in Table 2. No difference in objective response rate was observed between the sarcopenic and non-sarcopenic groups. The disease control rate in the sarcopenic group was significantly lower than that in the non-sarcopenic group [43.2% (19/44) vs 87.9% (87/99); P < 0.001]. Also, the median RDIs of gemcitabine and nab-paclitaxel until the first two cycles in the sarcopenic and non-sarcopenic groups were 79.6% and 80.6%, and 79.7% and 79.8%, respectively. There were no significant differences in the RDIs until the first two cycles for GnP chemotherapy between the sarcopenic and non-sarcopenic groups. In addition, the treatment courses after first-line GnP chemotherapy in enrolled patients are shown in Table 2. In the sarcopenic group, 45.9% of the patients received second-line chemotherapy and 54.1% received best supportive care. In the non-sarcopenic group, 76.3% of the patients received second-line chemotherapy, and 23.7% received best supportive care. Therefore, the patients in the sarcopenic group received significantly less second-line chemotherapy than those in the non-sarcopenic group (P = 0.004).
Survival
The Kaplan-Meier curves for OS and PFS according to sarcopenia status, as diagnosed by the 3D imaging system, are shown in Figure 3. The median OS of the sarcopenic and non-sarcopenic groups was 175 days and 562 days, respectively, and the patients in the sarcopenic group had a significantly poor OS than those in the non-sarcopenic group (P < 0.001; Figure 3A). Furthermore, the median PFS of the sarcopenic and non-sarcopenic groups was 88 and 242 days, respectively, and the patients in the sarcopenic group had a significantly poor PFS than those in the non-sarcopenic group (P < 0.001; Figure 3B). Also, the prognostic factors for OS and PFS were identified using the Cox proportional hazards model (Supplementary Tables 3-6). On univariate analysis, large tumor size (P = 0.011), head in location of tumor (P = 0.040), metastasis in clinical stage (P < 0.001), low albumin (P = 0.002), high CRP (P < 0.001), high CA19-9 (P = 0.007), low cholinesterase (P < 0.001), high m-GPS (P < 0.001), low PNI (P = 0.001), and sarcopenia (P < 0.001) were significantly associated with poor OS. To avoid multicollinearity among overlapping inflammatory and nutritional variables, these parameters were not included simultaneously in the same multivariate model. Multivariate analysis revealed that sarcopenia (HR = 2.89; 95%CI: 1.82-4.60, P < 0.001), metastasis in the clinical stage (HR = 2.25; 95%CI: 1.32-3.85, P = 0.003), and m-GPS (HR = 1.98; 95%CI: 1.22-3.19, P = 0.005) were independent significant clinical factors predicting poor OS. In addition, univariate analysis identified large tumor size (P = 0.003), metastasis in clinical stage (P < 0.001), high CA19-9 (P = 0.003), and sarcopenia (P < 0.001) as being significantly associated with PFS, and multivariate analysis revealed that sarcopenia (HR= 3.10; 95%CI: 1.87-5.12, P < 0.001) and metastasis in clinical stage (HR = 1.74; 95%CI: 1.07-2.85, P = 0.027) were independent significant clinical factors predicting poor PFS.
Figure 3 Kaplan-Meier curves for overall survival and progression-free survival in enrolled patients with and without sarcopenia.
A: The overall survival of the sarcopenic group (dotted blue line) was significantly shorter than that of the non-sarcopenic group (solid orange line) (P < 0.001, log-rank test). The median overall survival was 175 days and 562 days in the sarcopenic and non-sarcopenic groups, respectively; B: The progression-free survival of the sarcopenic group (dotted blue line) was significantly shorter than that of the non-sarcopenic group (solid orange line) (P < 0.001, log-rank test). The median progression-free survival was 88 days in the sarcopenic group and 242 days in the non-sarcopenic group.
Dynamic changes in sarcopenia and survival
Next, the impact of dynamic changes in sarcopenia, as assessed by skeletal muscle volume, on long-term prognosis was assessed in 135 patients whose skeletal muscle volume could be evaluated both before and 2 months after the initiation of GnP therapy. The results are shown in Figure 4. Among the 97 patients diagnosed with non-sarcopenia before GnP administration, 72 maintained their skeletal muscle volume for two months after treatment (non-sarcopenia maintenance group), while 25 subsequently developed sarcopenia at two months (sarcopenia progression group) (Figure 4A). Among the 38 patients diagnosed with sarcopenia before GnP administration, 35 maintained low skeletal muscle volume after two months of treatment (sarcopenia maintenance group), whereas three showed improvement in skeletal muscle volume (sarcopenia improvement group) (Figure 4A). Kaplan-Meier analysis was performed to compare OS among the non-sarcopenia maintenance, sarcopenia progression, and sarcopenia maintenance groups (Figure 4B). The non-sarcopenia maintenance group (median OS, 615 days) showed a significantly longer OS than the sarcopenia progression (median OS, 205 days) and sarcopenia maintenance groups (median OS, 185 days) (P < 0.001 and P < 0.001, respectively). In addition, there was no significant difference in OS between the sarcopenia progression and maintenance groups (P = 0.336).
Figure 4 Association between skeletal muscle volume dynamics and long-term prognosis.
A: Longitudinal changes in the number of sarcopenic and non-sarcopenic patients according to the psoas volume index before and two months after initiation of gemcitabine plus nab-paclitaxel chemotherapy. Colored boxes represent the patient groups; specifically, red, green, and blue boxes indicate patients who were non-sarcopenic at two months (including the non-sarcopenia maintenance and sarcopenia improvement groups), the sarcopenia progression group, and the sarcopenia maintenance group, respectively; B: Kaplan-Meier curves for overall survival (OS) according to sarcopenia dynamics. The OS of the non-sarcopenia-maintenance group (orange line) was significantly longer than those of the sarcopenia-progression group (green line) and the sarcopenia-maintenance group (blue line) (P < 0.001, log-rank test). The median OS in the non-sarcopenia-maintenance, sarcopenia-progression, and sarcopenia-maintenance groups were 615, 205, and 185 days, respectively.
Adverse events
GnP chemotherapy-related severe adverse events (> grade 3) in the enrolled patients are shown in Table 5. In the sarcopenic group, the incidence of severe adverse events was 47.8% (22/46), and severe hematologic and non-hematologic toxicities occurred in 34.8% (16/46) and 23.9% (11/46) of patients, respectively. In contrast, in the non-sarcopenic group, severe adverse events occurred in 26.9% (28/104) of patients, with severe hematologic and non-hematologic toxicities occurring in 14.4% (15/104) and 12.5% (13/104) of patients, respectively. Therefore, the incidence of severe adverse events (P = 0.015), especially severe hematologic toxicity (P = 0.001), was significantly higher in the sarcopenic group than in the non-sarcopenic group.
Table 5 Adverse events of grade 3 or 4 in the sarcopenic and non-sarcopenic patients, n (%).
In this study, we demonstrated that sarcopenia, diagnosed using a 3D image analysis system, was closely associated with a lower disease control rate, shorter TTF, poor prognosis (including OS and PFS), and a higher incidence of severe adverse events in older patients with unresectable PC who received first-line GnP therapy. Furthermore, our findings revealed that sarcopenia measured using a 3D image analysis system could be a useful clinical factor for predicting the tolerability and long-term prognosis of chemotherapy for PC. Also, the evaluation of dynamic changes in skeletal muscle volume demonstrated that the progression of sarcopenia during chemotherapy was strongly associated with a shorter OS. To our knowledge, there have been few previous reports evaluating the impact of skeletal muscle volume measurement using a 3D image analysis system on chemotherapy response in older patients with unresectable PC who received GnP therapy, as in the present study.
In the management of patients with PC, well-validated clinical prognostic models play an important role in predicting life expectancy, guiding treatment strategies, and educating patients and their families. Various factors, including pathological predisposition, patient background, and treatment regimens, may be closely related to treatment tolerance, efficacy, and long-term prognosis in patients with PC. Previous reports have identified several clinical parameters, including ECOG PS, obesity, CA19-9, carcinoembryonic antigen, CRP, and albumin, as prognostic factors for PC[26-34]. However, these findings differ among previous reports, and the established evidence for prognostic factors remains unclear. Previously, Proctor et al[35] demonstrated in a meta-analysis that mGPS, an indicator of inflammation and nutritional status, is closely associated with long-term prognosis, including OS and PFS, in patients with various cancers. In addition, it has been reported that hypoalbuminemia could be a risk factor for the development of adverse outcomes in patients with gastrointestinal cancers[25,36-38]. These results may reflect cancer-associated inflammatory responses in cancer patients, such as transforming growth factor-β (TGF-β) and interleukin (IL)-6, which promote tumorigenesis that enhance the proliferation, metastasis, and immune escape of tumor cells[39,40]. However, in this study, several inflammatory and nutritional mediators, including the mGPS, NLR, and PNI, were not significantly associated with tolerability or long-term prognosis in patients with advanced PC who received first-line GnP therapy. In PC, these mediators may not necessarily reflect the disease state because they are masked by chronic inflammation in the bile duct and pancreas. In this study, we found that sarcopenia derived from a 3D image analysis system was a useful and clinically relevant predictor of TTF, OS, and PFS in patients with advanced PC before chemotherapy. Furthermore, longitudinal monitoring of skeletal muscle volume provides valuable insights for predicting long-term prognosis.
Sarcopenia is closely associated with a poor long-term prognosis in patients with several types of cancer. Several studies have suggested that sarcopenia is associated with increased chemotherapy toxicity, poor OS, and poor PFS[14-17]. On the other hand, Lellouche et al[18] showed that sarcopenia did not affect the long-term prognosis, including OS and PFS, or the incidence of severe adverse events in patients with metastatic PC. The inconsistency in these results may depend on the patient- and cancer-related backgrounds, including race and chemotherapy regimens. In addition, the inaccuracy in diagnosing sarcopenia may have contributed to these discrepancies. Indeed, most previous papers diagnosed sarcopenia using the cross-sectional area of skeletal muscle at the L3 lumbar level[17-21]. However, 2D muscle mass parameters obtained using this measurement method may reflect only a small portion of the psoas muscle. Therefore, this cross-sectional analysis method could yield large discrepancies depending on muscle position, potentially contributing to inaccuracies in sarcopenia diagnosis. Novel measurement methods using specialized techniques may be required to assess the skeletal muscle mass accurately. In addition, most prior studies evaluated sarcopenia only at baseline without considering the dynamic changes in skeletal muscle during chemotherapy. In this study, we quantified skeletal muscle mass using a 3D volumetric system to assess sarcopenia more accurately. We suggest that for diagnosing sarcopenia, the muscle volumetric analysis method is more reasonable because it can comprehensively measure a wider range of the psoas muscle and has lower statistical error. In addition, a 3D image analysis system can quickly and automatically calculate skeletal muscle volume using an analysis program, thereby enabling a simpler, more objective diagnosis of sarcopenia. Bimurzayeva et al[22] demonstrated that 3D volume parameters calculated using an automated program were more strongly correlated with long-term prognosis in patients with rectal cancer than 2D parameters. Therefore, 3D volumetric analysis may provide a more robust and reproducible evaluation of skeletal muscle mass than conventional 2D cross-sectional assessment, potentially reducing measurement variability. To the best of our knowledge, few previous studies have evaluated the impact of skeletal muscle mass using 3D volumetric parameters on the long-term prognosis of patients with advanced PC receiving chemotherapy. Moreover, this study extends prior findings by incorporating early skeletal muscle dynamics during treatment, while focusing specifically on older patients receiving first-line GnP therapy, thereby providing additional clinically relevant insights beyond baseline sarcopenia assessment alone. This study found that sarcopenia, which was more accurately diagnosed using a 3D image analysis system, could be a useful clinical factor in predicting the tolerance and prognosis of older patients with advanced PC receiving first-line GnP therapy.
There are only a few reports on the mechanism of the association between sarcopenia and poor oncological outcomes in patients with several advanced cancers. One of them is that sarcopenia by low skeletal muscle mass may induce immunosenescence, which is involved in cancer progression and systemic inflammation[41-43]. Systemic inflammation by inflammatory mediators such as tumor necrosis factor-α, IL-6, and IL-1, which are involved in oncogenesis and cancer progression, leads to promote cancer cell survival and metastatic transformation[44,45]. In addition, these cytokines may contribute to the further progression of sarcopenia by upregulating proinflammatory cytokines and increasing muscle catabolism[46,47]. Also, skeletal muscle is a secretory organ, and muscle cells are known to produce and secrete several hundred cytokines, peptides, and myokines that influence various systemic responses[48]. Among numerous myokines, myostatin, a member of the TGF-β superfamily, may regulate skeletal muscle mass and promote cancer progression. Specifically, skeletal muscle decline suppresses the anti-tumor immune response through increased TGF-β levels, leading to cancer promotion and recurrence[49,50]. Furthermore, skeletal muscles promote immune function by signaling via IL-15 in cell-to-cell interactions[51]. IL-15 modulates the proliferation, activation, and distribution of natural killer and CD8+ cells, which play major roles in the exhaustion and elimination of tumor cells[52]. Therefore, in patients with sarcopenia, these suppression of anti-tumor immunity due to skeletal muscle deterioration could promote tumor progression from an earlier cancer stage. Further research is essential to clarify the mechanism by which sarcopenia is associated with poor prognosis in patients with advanced cancer.
Several studies have suggested strategies for improving sarcopenia, including nutritional support, resistance exercise, and pharmacological agents[53]. A randomized controlled trial showed that resistance exercise with adequate nutritional support, including protein, vitamin preparations, and calcium, contributed to improved skeletal muscle mass in community-dwelling older individuals[54]. Also, medications such as anamorelin, an orally active selective ghrelin receptor agonist, have been shown to be associated with increased muscle mass, weight gain, and improved appetite in patients with gastrointestinal cancers, including PC[55]. In addition, a meta-analysis revealed that in patients with PC, exercise training to prevent sarcopenia is both safe and flexible, and could provide a beneficial effect on various physical and psychological outcomes[56]. In view of these above findings, prehabilitation, including interventions focusing on physical activity, nutrition, and psychological support, may be important for improving sarcopenia, which leads to reduced complications and enhanced quality of life for patients with cancer[45]. However, there is no clear evidence that rehabilitation and nutritional support during chemotherapy contribute to maintaining muscle mass, reducing the adverse events of chemotherapy, and enabling the continuation of chemotherapy in older patients with advanced PC. We demonstrated that monitoring changes in skeletal muscle volume over time revealed that sarcopenia progression during chemotherapy was significantly associated with poor long-term prognosis. This finding suggests that maintaining skeletal muscle volume is crucial in older patients with advanced PC receiving GnP treatment. Therefore, we suggest that the early recognition of sarcopenia, possible intervention of muscle mass, and nutritional support may help to prevent muscle wasting and to improve the long-term prognosis of patients with PC. Large-scale clinical studies are necessary to establish treatment strategies for sarcopenia in patients with advanced cancer receiving chemotherapy.
This study had several limitations. First, this was a retrospective study with a limited number of Asian individuals at a single institution, which may have introduced selection bias and limited the generalizability of the findings. In the future, a larger, prospective, multicenter study would be necessary to further confirm our findings. In addition, although skeletal muscle measurements were confirmed by multiple expert gastroenterologists using a semi-automated 3D system, the lack of radiologist involvement may represent a minor methodological limitation. Second, the threshold values for sarcopenia based on the skeletal muscle volume remain unclear. Although previous reports have recommended cutoff values for various methods of skeletal muscle measurement, including the skeletal muscle index method using CT and the bioelectrical impedance analysis method[10], a standard cutoff value of skeletal muscle volume for sarcopenia has not been established. In addition, there may be marked differences in physical function between Western and Asian populations. Therefore, we used a PVI value of 61.5 cm3/m3 for men and 44.1 cm3/m3 for women as the most appropriate cutoff value for sarcopenia in this study, based on previous studies in Asian cohorts[25]. It may be important to set a PVI cutoff value that is more suitable for Japanese patients with PC.
CONCLUSION
In conclusion, skeletal muscle assessment using a 3D image analysis system was useful in predicting the clinical response to chemotherapy in older patients with unresectable PC who received first-line GnP therapy. Our findings suggest that in the future, assessing skeletal muscle volume before and during chemotherapy could help stratify patients for treatment strategy, which may lead to improved prognosis.
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