Abstract
Background
Insufficient evidence exists regarding the characteristics of elderly patients with presarcopenia and their prognosis. Therefore, we aim to investigate the impact of preoperative presarcopenia on postoperative outcomes in elderly patients with resectable colorectal cancer.
Methods
We included patients aged ≥ 75 years who underwent curative resection between June 2009 and December 2019. The psoas muscle index was calculated based on the computed tomography scan at the L3 level (lumbar area). The primary outcome was the difference in overall survival based on the presence or absence of presarcopenia. The secondary outcomes included differences in the occurrence of postoperative complications, tumor recurrence, and the impact of adjuvant chemotherapy on survival rates in high-risk stage II cancer.
Results
We included 325 patients (presarcopenia: 63) in this study. The presarcopenia group was older than the normal group (p = 0.02), with a lower body mass index (p < 0.001). Preoperative blood test results indicated a higher frequency of anemia (p = 0.002), hypoalbuminemia (p = 0.009), and a higher neutrophil-to-lymphocyte ratio (p = 0.012) in the presarcopenia group. Postoperative complications did not differ significantly between the two groups (p = 0.989). In multivariate analysis, presarcopenia emerged as a significant factor affecting overall survival (HR 1.75, 95% CI 1.15–2.67, p = 0.009), but not recurrence-free survival (HR 1.48, 95% CI 0.86–2.55, p = 0.156). Presarcopenia in high-risk stage II colorectal cancer appeared to be a factor where adjuvant chemotherapy did not influence overall survival (HR 1.70, 95% CI 0.40 – 7.26, p = 0.475).
Conclusion
In patients with poor overall survival associated with presarcopenia, adjuvant chemotherapy should be selectively considered.
Keywords: Sarcopenia, Colorectal neoplasms, Survival, Postoperative complications, Adjuvant chemotherapy, Recurrence
Introduction
Generally, decline in muscle mass is inevitable as part of the aging process [1]. However, the extent of muscle loss can vary due to factors, such as an individual's nutritional status and level of physical activity [2–4]. Therefore, when deciding on a treatment plan for elderly patients, consideration should be given to indicators of biologic aging, such as the extent of muscle mass loss, rather than relying solely on chronological age, which is a mere numerical value [5].
A patient’s overall condition can impact colorectal cancer treatment and outcomes. Presarcopenia, a factor reflecting a patient’s overall condition, reportedly influences prognosis [6–9]. However, research on the clinical impact of presarcopenia in elderly patients with colorectal cancer is scarce. Moreover, in elderly patients with a high prevalence of presarcopenia, objective evidence regarding the effect of presarcopenia on short- and long-term postoperative outcomes is lacking. Additionally, owing to the high frequency of chemotherapy-associated toxicity in elderly patients [10], insufficient evidence is available to guide decisions, including when to administer adjuvant chemotherapy.
Therefore, our study aims to investigate the impact of preoperative presarcopenia on short- and long-term postoperative outcomes in elderly patients with resectable colorectal cancer.
Methods
This study was approved by the institutional review board (IRB) of the Catholic University of Korea and was performed in accordance with the IRB’s guidelines and regulations (UC21RISI0035). The requirement for informed consent was waived by the IRB of the Catholic University of Korea.
Patients
We included patients aged 75 years and older diagnosed with colorectal cancer at Uijeongbu St. Mary's Hospital who underwent surgery between June 2009 and December 2019. The exclusion criteria included cases where obtaining computed tomography (CT) images for measuring the psoas muscle index was challenging and cases of local excision for early rectal cancer or surgery for stage IV cancer (palliative colostomy, bypass surgery, primary tumor resection or primary tumor resection with metastatectomy).
Definition of presarcopenia
Using the CoreSlicer program (https://coreslicer.com), the psoas muscle index was calculated from the CT scan at the L3 level (lumbar area). The cut-off values for presarcopenia were set at 4.24 cm2/m2 in men and 2.50 cm2/m2 in women [11]. The presarcopenia group in our study includes patients who may potentially be classified as having sarcopenia, had functional data been available [12].
Primary and secondary outcomes
The primary outcome was the difference in overall survival (OS) based on the presence or absence of presarcopenia. The secondary outcomes included differences in postoperative complications, recurrence free survival (RFS), and the impact of adjuvant chemotherapy on survival rates in high-risk stage II colorectal cancer based on the presence or absence of presarcopenia. The final survival confirmation was based on patient mortality information obtained from the Korea National Cancer Center (Central Cancer Registry) as of May 16, 2023. The patients’ last hospital visit dat was considered the last follow-up date for confirming recurrence status.
Statistical analysis
For comparative analysis between the two groups based on the presence or absence of presarcopenia, continuous variables were analyzed using either Student's t-test or the Mann–Whitney U test, while categorical variables were analyzed using the Chi-square test, Fisher’s exact test, or linear-by-linear association. Categorical variables were reported as numbers and percentages, and distribution of continuous characteristics was reported as mean ± standard deviation (SD).
Kaplan–Meier analyses with log-rank tests were conducted for comparing recurrence-free survival and OS. Additionally, Cox regression analyses were performed to evaluate factors influencing RFS and OS. Univariable analyses were conducted for descriptive and exploratory purposes. Multivariable Cox regression models were constructed using prespecified clinically relevant covariates selected a priori based on clinical relevance and biological plausibility.
As a sensitivity analysis, univariable Cox regression analyses were first performed for all available clinically relevant variables. Variables demonstrating a p-value < 0.1 in univariable analyses were eligible for inclusion. The model was subsequently simplified using a backward likelihood ratio (LR) approach, and the final multivariable results reflect only those covariates that remained after this process. This sensitivity analysis was performed solely to assess the robustness of the primary prespecified models and was not intended to define the main analytical conclusions.
All statistical analysis was conducted using SPSS version 21.0 (IBM Corp, Armonk, NY, USA), and a significance level of p < 0.05 was considered statistically significant.
Results
A total of 101 individuals were excluded based on the exclusion criteria, resulting in 325 patients included in our analysis (normal: 262, presarcopenia: 63) (Fig. 1).
Fig. 1.
Flow chart of patient selection
Characteristics of patients with presarcopenias
In the baseline characteristics, the presarcopenia group was found to be older than the normal group (81.6 ± 4.7 versus 80.1 ± 4.3, p = 0.02), with a lower body mass index (22.0 ± 3.4 vs. 23.6 ± 4.0, p < 0.001) and a higher prevalence of a history of cerebral vascular accident (12 [4.6%] vs. 9 [14.3%], p = 0.009) (Table 1).
Table 1.
Clinical characteristics of the normal and presarcopenia groups
| Normal (n = 262) | Presarcopenia (n = 63) | p-value | |
|---|---|---|---|
| Age (years) | 80.1 ± 4.3 | 81.6 ± 4.7 | 0.02 |
| Sex | 0.753 | ||
| Male | 143 (54.6%) | 33 (52.4%) | |
| Female | 119 (45.4%) | 30 (47.6%) | |
| Height (cm) | 157.7 ± 9.6 | 160.0 ± 10.7 | 0.105 |
| Weight (kg) | 58.8 ± 11.0 | 54.1 ± 11.5 | 0.003 |
| BMI (kg/m2) | 23.6 ± 4.0 | 22.0 ± 3.4 | < 0.001 |
| Diabetes | 60 (22.9%) | 11 (17.5%) | 0.348 |
| Hypertension | 165(63.0%) | 34 (54.0%) | 0.188 |
| Heart disease | 41 (15.6%) | 8 (12.7%) | 0.557 |
| Pulmonary disease | 35 (13.4%) | 12 (19.0%) | 0.249 |
| Liver disease | 2 (0.8%) | 1 (1.6%) | 0.477 |
| Cerebral vascular accident | 12 (4.6%) | 9 (14.3%) | 0.009 |
| ASA classification | 0.127 | ||
| 1 | 7 (2.7%) | 2 (3.2%) | |
| 2 | 186 (71.0%) | 38 (60.3%) | |
| 3 | 64 (24.4%) | 20 (31.7%) | |
| 4 | 4 (1.5%) | 3 (4.8%) | |
| 5 | 1 (0.4%) | 0 | |
| Smoking | 48(18.3%) | 6 (9.5%) | 0.092 |
| Alcohol | 30 (11.5%) | 7 (11.1%) | 0.939 |
| NLR | 5.4 ± 2.4 | 6.5 ± 3.3 | 0.012 |
| Cancer location | 0.198 | ||
| Right | 95 (36.3%) | 30 (47.6%) | |
| Left | 95 (36.3%) | 17 (27.0%) | |
| Rectum | 69 (26.3%) | 14 (22.2%) | |
| Synchronous | 3 (1.1%) | 2 (3.2%) | |
| Emergency surgery | 13 (5.0%) | 5 (7.9%) | 0.36 |
| Obstruction | 58 (22.1%) | 24 (38.1%) | 0.009 |
| Perforation | 20 (7.6%) | 12 (19.0%) | 0.006 |
| Operation type | 0.082 | ||
| Open | 69 (26.3%) | 25 (39.7%) | |
| Laparoscopy | 176 (67.2%) | 33 (52.4%) | |
| Conversion | 17 (6.5%) | 5 (7.9%) | |
| Anemia | 166 (63.6%) | 53 (84.1%) | 0.002 |
| Albumin | 0.009 | ||
| Normal | 190 (72.5%) | 35 (55.6%) | |
| Hypoalbuminemia | 72 (27.5%) | 28 (44.4%) | |
| RBC transfusion | |||
| Preoperative | 21 (8.0%) | 11 (17.5%) | 0.024 |
| Intraoperative | 38 (14.5%) | 13 (20.6%) | 0.23 |
| Total surgical time (min) | 205.3 ± 69.0 | 195.9 ± 63.8 | 0.324 |
| Postoperative complication (Clavien-Dindo classification) | 0.989 | ||
| 0 | 179 (68.3%) | 39 (61.9%) | |
| 1 | 10 (3.8%) | 5 (7.9%) | |
| 2 | 54 (20.6%) | 16 (25.4%) | |
| 3a | 6 (2.3%) | 2 (3.2%) | |
| 3b | 5 (1.9%) | 0 | |
| 4 | 5 (1.9%) | 1 (1.6%) | |
| 5 | 3 (1.1%) | 0 | |
| Tumor size (cm) | 4.4 ± 2.9 | 4.7 ± 2.4 | 0.469 |
| Pathologic stage | 0.181 | ||
| 0 | 3 (1.1%) | 1 (1.6%) | |
| 1 | 56 (21.4%) | 5 (7.9%) | |
| 2 | 104 (39.7%) | 32 (50.8%) | |
| 3 | 99 (37.8%) | 25 (39.7%) | |
| Pathologic T | 0.007 | ||
| Tis | 3 (1.1%) | 1 (1.6%) | |
| 1 | 27 (10.3%) | 2 (3.2%) | |
| 2 | 40 (15.3%) | 3 (4.8%) | |
| 3 | 172 (65.6%) | 48 (76.2%) | |
| 4 | 20 (7.6%) | 9 (14.3%) | |
| Pathologic N | 0.874 | ||
| 0 | 163 (62.2%) | 38 (60.3%) | |
| 1 | 64 (24.4%) | 15 (23.8%) | |
| 2 | 35 (13.4%) | 10 (15.9%) | |
| Lymphatic invasion | 86 (34.4%) | 28 (45.2%) | 0.115 |
| Venous invasion | 38 (15.3%) | 9 (15.0%) | 0.95 |
| Perineural invasion | 51 (20.6%) | 14 (23.3%) | 0.637 |
| Differentiation | 0.119 | ||
| Well | 44 (17.3%) | 6 (9.5%) | |
| Moderate | 199 (78.0%) | 52 (82.5%) | |
| Poor | 8 (3.1%) | 4 (6.3%) | |
| Mucinous | 4 (1.6%) | 1 (1.6%) |
ASA The American Society of Anesthesiologists (ASA) physical status, RBC Red blood cell, BMI Body mass index, NLR Neutrophil-to-lymphocyte ratio
Patients in the presarcopenia group also had a higher incidence of tumor-related obstruction (p = 0.009) and perforation (p = 0.006). Preoperative blood test results indicated a higher frequency of anemia (p = 0.002), hypoalbuminemia (p = 0.009), and a higher neutrophil-to-lymphocyte ratio (NLR) (p = 0.012) in the presarcopenia group (Table 1).
Final pathologic report showed a higher T stage in the presarcopenia group (p = 0.007) (Table 1). Adjuvant chemotherapy was administered to 140 individuals (43.1%), with a significant difference between the normal (120/262, 45.8%) and presarcopenia group (20/63, 19.4%) (p = 0.043). Excluding four patients with unknown chemotherapy completion status, the completion rates in the normal and presarcopenia groups were 63.2% and 36.8%, respectively (p = 0.03). Among the 136 patients who underwent chemotherapy, there were 117 patients (86.0%) in the normal group and 19 patients (14.0%) in the presarcopenia group. Completion of the planned chemotherapy was observed in 74 patients (63.2%) within the normal group, while only 7 patients (36.8%) in the presarcopenia group completed the treatment course (p = 0.03).
Primary outcome
During a median follow-up period of 56 months (interquartile range, 27–84 months), the 3-year overall survival rates were 86.6% in the normal group and 49.2% in the presarcopenia group, while the 5-year overall survival rates were 77.9% and 47.2%, respectively (log-rank p = 0.001) (Fig. 2). In univariate analyses, older age, higher ASA classification, advanced pathologic stage, and presarcopenia were significantly associated with worse overall survival (Table 2). In multivariate analysis, presarcopenia remained independently associated with poorer overall survival (Hazard ratio (HR) 1.75, 95% Confidence interval(CI) 1.15–2.67, p = 0.009) after adjustment for age, sex, ASA classification, and pathologic stage(Table 2). Advanced pathologic stage (stage III vs. stage 0–I: HR 2.56, 95% CI 1.38–4.77, p = 0.003) and higher ASA classification were also independently associated with overall survival, whereas age and sex showed borderline significance.
Fig. 2.
Kaplan–Meier curves for overall survival in the nonpresarcopenia and presarcopenia
Table 2.
Factors affecting overall survival
| Univariate analysis | Multivariate analysis | |||||||
|---|---|---|---|---|---|---|---|---|
| Hazard ratio | 95% Confidence interval | p-value | Hazard ratio | 95% Confidence interval | p-value | |||
| Lower limit | Upper limit | Lower limit | Upper limit | |||||
| Age (years) | 1.05 | 1.01 | 1.09 | 0.013 | 1.04 | 1.00 | 1.08 | 0.056 |
| Sex | ||||||||
| Male | Reference | |||||||
| Female | 0.83 | 0.58 | 1.20 | 0.322 | 0.71 | 0.48 | 1.04 | 0.079 |
| ASA classification | < 0.001 | < 0.001 | ||||||
| 1 | Reference | |||||||
| 2 | 1.51 | 0.37 | 6.17 | 0.564 | 1.49 | 0.36 | 6.14 | 0.581 |
| 3 | 2.49 | 0.60 | 10.31 | 0.208 | 2.08 | 0.50 | 8.70 | 0.317 |
| 4 | 18.46 | 3.79 | 89.98 | < 0.001 | 18.22 | 3.64 | 91.26 | < 0.001 |
| 5 | 49.01 | 4.21 | 571.23 | 0.002 | 73.94 | 6.00 | 911.01 | 0.001 |
| Smoking | 0.90 | 0.55 | 1.47 | 0.666 | ||||
| Alcohol | 1.04 | 0.60 | 1.82 | 0.885 | ||||
| Cancer location | 0.432 | |||||||
| Right | Reference | |||||||
| Left | 0.78 | 0.51 | 1.19 | 0.250 | ||||
| Rectum | 0.84 | 0.53 | 1.32 | 0.440 | ||||
| Synchronous | 1.73 | 0.54 | 5.54 | 0.359 | ||||
| Stage | 0.003 | |||||||
| 0,1 | Reference | 0.004 | ||||||
| 2 | 2.06 | 1.12 | 3.79 | 0.020 | 1.62 | 0.87 | 3.03 | 0.132 |
| 3 | 2.81 | 1.53 | 5.13 | 0.001 | 2.56 | 1.38 | 4.77 | 0.003 |
| Presarcopenia | 1.99 | 1.33 | 2.97 | 0.001 | 1.75 | 1.15 | 2.67 | 0.009 |
ASA The American Society of Anesthesiologists (ASA) physical status
† Multivariable Cox regression for overall survival was based on prespecified covariates (age, sex, ASA classification, pathological stage, and presarcopenia), retained regardless of statistical significance
Secondary outcomes
The frequency of postoperative complications using the Clavien–Dindo classification did not show a statistically significant difference between the two groups (p = 0.989). When a Kaplan–Meier curve was plotted for RFS, the presarcopenia group exhibited a higher incidence of recurrence compared to the normal group (3-year recurrence-free survival rate: 64.2% vs. 75.0%, p = 0.017) (Fig. 3). In univariable analyses for RFS, age, synchronous tumors, advanced pathological stage, and presarcopenia were significantly associated with recurrence (Table 3). In multivariable analysis, synchronous tumors (HR 5.81, 95% CI 1.69–20.00, p = 0.005) and advanced pathologic stage (stage III vs. stage 0–I: HR 4.96, 95% CI 2.07–11.88, p < 0.001) remained independently associated with RFS (Table 3). Presarcopenia was not an independent predictor of recurrence after adjustment for tumor-related factors (HR 1.48, 95% CI 0.86–2.55, p = 0.156).
Fig. 3.
Kaplan–Meier curves for recurrence in the nonpresarcopenia and presarcopenia
Table 3.
Factors affecting recurrence-free survival
| Univariate analysis | Multivariate analysis | |||||||
|---|---|---|---|---|---|---|---|---|
| Hazard ratio | 95% Confidence interval | p-value | Hazard ratio | 95% Confidence interval | p-value | |||
| Lower limit | Upper limit | Lower limit | Upper limit | |||||
| Age (years) | 1.08 | 1.03 | 1.14 | 0.003 | 1.06 | 1.00 | 1.12 | 0.055 |
| Sex | ||||||||
| Male | Reference | |||||||
| Female | 0.96 | 0.61 | 1.52 | 0.860 | ||||
| ASA classification | ||||||||
| 1,2 | Reference | |||||||
| 3–5 | 0.96 | 0.56 | 1.66 | 0.890 | ||||
| Smoking | 0.86 | 0.44 | 1.67 | 0.649 | ||||
| Alcohol | 0.67 | 0.29 | 1.54 | 0.342 | ||||
| Cancer location | 0.009 | |||||||
| Right | Reference | 0.005 | ||||||
| Left | 0.62 | 0.34 | 1.12 | 0.113 | 0.63 | 0.35 | 1.16 | 0.140 |
| Rectum | 1.16 | 0.68 | 1.97 | 0.597 | 1.15 | 0.67 | 1.98 | 0.605 |
| Synchronous | 4.73 | 1.43 | 15.63 | 0.011 | 5.81 | 1.69 | 20.00 | 0.005 |
| Stage | < 0.001 | < 0.001 | ||||||
| 0,1 | Reference | |||||||
| 2 | 2.73 | 1.12 | 6.64 | 0.027 | 2.39 | 0.97 | 5.92 | 0.059 |
| 3 | 5.74 | 2.43 | 13.56 | < 0.001 | 4.96 | 2.07 | 11.88 | < 0.001 |
| Presarcopenia | 1.89 | 1.11 | 3.22 | 0.020 | 1.48 | 0.86 | 2.55 | 0.156 |
ASA The American Society of Anesthesiologists (ASA) physical status
†For recurrence-free survival, multivariable adjustment focused on tumor-related factors; ASA physical status was dichotomized to improve model stability
Sensitivity analysis for OS
In the analysis of factors influencing OS, we first conducted univariate analysis to select variables with a p-value < 0.1. Subsequently, these chosen variables were used for multivariate analysis, revealing that presarcopenia (HR 1.65, 95% CI 1.08–2.51, p = 0.021) emerged as a significant factor affecting OS. Additionally, other variables, such as pulmonary disease (HR 2.03, 95% CI 1.28–3.22, p = 0.003) and the American Society of Anesthesiologists (ASA) physical status classification (p < 0.001) were identified as significant contributors to OS (Table 4).
Table 4.
Sensitivity analysis of factors associated with overall survival
| Univariate analysis | Multivariate analysis | |||||||
|---|---|---|---|---|---|---|---|---|
| Hazard ratio | 95% Confidence interval | p-value | Hazard ratio | 95% Confidence interval | p-value | |||
| Lower limit | Upper limit | Lower limit | Upper limit | |||||
| Age (years) | 1.05 | 1.01 | 1.09 | 0.013 | ||||
| Sex | ||||||||
| Male | Reference | |||||||
| Female | 0.83 | 0.58 | 1.20 | 0.322 | ||||
| BMI (kg/m2) | < 0.001 | |||||||
| < 20 | Reference | |||||||
| 20–25 | 0.57 | 0.38 | 0.87 | 0.008 | ||||
| > 25 | 0.36 | 0.22 | 0.61 | < 0.001 | ||||
| Diabetes | 0.87 | 0.56 | 1.36 | 0.548 | ||||
| Hypertension | 0.78 | 0.54 | 1.12 | 0.175 | ||||
| Heart disease | 1.34 | 0.84 | 2.12 | 0.218 | ||||
| Pulmonary disease | 2.48 | 1.63 | 3.76 | < 0.001 | 2.03 | 1.28 | 3.22 | 0.003 |
| Liver disease | 1.03 | 0.14 | 7.39 | 0.974 | ||||
| Cerebral vascular accident | 1.62 | 0.87 | 3.01 | 0.129 | ||||
| ASA classification | < 0.001 | < 0.001 | ||||||
| 1 | Reference | |||||||
| 2 | 1.51 | 0.37 | 6.17 | 0.564 | 1.57 | 0.37 | 6.65 | 0.539 |
| 3 | 2.49 | 0.60 | 10.31 | 0.208 | 2.08 | 0.47 | 9.10 | 0.332 |
| 4 | 18.46 | 3.79 | 89.98 | < 0.001 | 16.55 | 3.13 | 87.57 | 0.001 |
| 5 | 49.01 | 4.21 | 571.23 | 0.002 | 77.01 | 6.11 | 970.42 | 0.001 |
| Smoking | 0.90 | 0.55 | 1.47 | 0.666 | ||||
| Alcohol | 1.04 | 0.60 | 1.82 | 0.885 | ||||
| NLR | 1.36 | 0.93 | 1.97 | 0.109 | ||||
| Cancer location | 0.432 | |||||||
| Right | Reference | |||||||
| Left | 0.78 | 0.51 | 1.19 | 0.250 | ||||
| Rectum | 0.84 | 0.53 | 1.32 | 0.440 | ||||
| Synchronous | 1.73 | 0.54 | 5.54 | 0.359 | ||||
| Emergency surgery | 2.12 | 1.11 | 4.06 | 0.023 | ||||
| Obstruction | 1.35 | 0.91 | 2.01 | 0.131 | ||||
| Perforation | 2.21 | 1.34 | 3.65 | 0.002 | ||||
| Operation type | < 0.001 | 0.198 | ||||||
| Open | Reference | |||||||
| Laparoscopy | 0.42 | 0.29 | 0.60 | < 0.001 | 0.69 | 0.46 | 1.04 | 0.078 |
| Conversion | 0.52 | 0.25 | 1.09 | 0.084 | 0.68 | 0.30 | 1.52 | 0.341 |
| Anemia | 1.41 | 0.94 | 2.11 | 0.098 | ||||
| Albumin | ||||||||
| Normal | Reference | |||||||
| Hypoalbuminemia | 1.55 | 1.07 | 2.24 | 0.020 | ||||
| RBC transfusion | ||||||||
| Preoperative | 1.15 | 0.64 | 2.04 | 0.643 | ||||
| Intraoperative | 1.32 | 0.83 | 2.12 | 0.246 | ||||
| Stage | 0.003 | |||||||
| 0,1 | Reference | |||||||
| 2 | 2.06 | 1.12 | 3.79 | 0.020 | ||||
| 3 | 2.81 | 1.53 | 5.13 | 0.001 | ||||
| T stage | ||||||||
| Tis −2 | Reference | |||||||
| 3,4 | 2.49 | 1.45 | 4.28 | 0.001 | 1.63 | 0.91 | 2.90 | 0.100 |
| N stage | 0.021 | 0.057 | ||||||
| 0 | Reference | |||||||
| 1 | 1.58 | 1.05 | 2.39 | 0.029 | 1.57 | 1.01 | 2.45 | 0.047 |
| 2 | 1.78 | 1.09 | 2.91 | 0.022 | 1.67 | 0.99 | 2.82 | 0.057 |
| Lymphatic invasion | 1.61 | 1.12 | 2.32 | 0.011 | ||||
| Venous invasion | 1.35 | 0.83 | 2.19 | 0.224 | ||||
| Perineural invasion | 1.39 | 0.90 | 2.13 | 0.134 | ||||
| Differentiation | 0.057 | 0.083 | ||||||
| Well | Reference | |||||||
| Moderate | 0.88 | 0.54 | 1.43 | 0.612 | 0.68 | 0.40 | 1.15 | 0.151 |
| Poor | 2.17 | 0.96 | 4.94 | 0.064 | 1.62 | 0.67 | 3.90 | 0.285 |
| Mucinous | 1.98 | 0.59 | 6.66 | 0.271 | 1.55 | 0.44 | 5.44 | 0.491 |
| Adjuvant Chemotherapy | 0.76 | 0.53 | 1.09 | 0.139 | ||||
| Chemotherapy completion | 0.39 | 0.22 | 0.70 | 0.001 | ||||
| Presarcopenia | 1.99 | 1.33 | 2.97 | 0.001 | 1.65 | 1.08 | 2.51 | 0.021 |
ASA The American Society of Anesthesiologists (ASA) physical status, RBC Red blood cell, BMI Body mass index, NLR Neutrophil-to-lymphocyte ratio
Sensitivity analysis for RFS
Similar to the analysis for factors affecting OS, univariate analysis for recurrence-free survival was conducted. Presarcopenia showed an HR of 1.89 (95% CI 1.11–3.22, p = 0.020) in univariate analysis, but it did not emerge as a significant factor in multivariate analysis. Instead, synchronous tumor (p = 0.001), T3-4 (p = 0.023), perineural invasion (p = 0.011), and tumor differentiation (p = 0.006) were identified as significant factors influencing recurrence-free survival (Table 5).
Table 5.
Sensitivity analysis of factors associated with recurrence-free survival
| Univariate analysis | Multivariate analysis | |||||||
|---|---|---|---|---|---|---|---|---|
| Hazard ratio | 95% Confidence interval | p-value | Hazard ratio | 95% Confidence interval | p-value | |||
| Lower limit | Upper limit | Lower limit | Upper limit | |||||
| Age (years) | 1.08 | 1.03 | 1.14 | 0.003 | 1.05 | 0.99 | 1.12 | 0.099 |
| Sex | ||||||||
| Male | Reference | |||||||
| Female | 0.96 | 0.61 | 1.52 | 0.860 | ||||
| BMI (kg/m2) | 0.030 | |||||||
| 20–25 | Reference | |||||||
| < 20 | 1.07 | 0.59 | 1.95 | 0.830 | ||||
| > 25 | 0.46 | 0.25 | 0.84 | 0.012 | ||||
| Diabetes | 1.11 | 0.64 | 1.91 | 0.714 | ||||
| Hypertension | 1.06 | 0.66 | 1.7 | 0.808 | ||||
| Heart disease | 0.94 | 0.48 | 1.83 | 0.851 | ||||
| Pulmonary disease | 1.69 | 0.89 | 3.22 | 0.112 | ||||
| Liver disease | 3.66 | 0.89 | 15.01 | 0.071 | ||||
| Cerebral vascular accident | 1.24 | 0.5 | 3.09 | 0.638 | ||||
| ASA classification | ||||||||
| 1,2 | Reference | |||||||
| 3–5 | 0.96 | 0.56 | 1.66 | 0.890 | ||||
| Smoking | 0.86 | 0.44 | 1.67 | 0.649 | ||||
| Alcohol | 0.67 | 0.29 | 1.54 | 0.342 | ||||
| NLR | 1.12 | 0.7 | 1.78 | 0.633 | ||||
| Cancer location | 0.009 | 0.020 | ||||||
| Right | Reference | |||||||
| Left | 0.62 | 0.34 | 1.12 | 0.113 | 0.68 | 0.36 | 1.31 | 0.252 |
| Rectum | 1.16 | 0.68 | 1.97 | 0.597 | 1.14 | 0.64 | 2.03 | 0.663 |
| Synchronous | 4.73 | 1.43 | 15.63 | 0.011 | 8 | 2.27 | 28.24 | 0.001 |
| Emergency surgery | 1.06 | 0.26 | 4.32 | 0.938 | ||||
| Obstruction | 1.19 | 0.7 | 2.02 | 0.532 | ||||
| Perforation | 1.89 | 0.94 | 3.8 | 0.075 | ||||
| Operation type | 0.563 | |||||||
| Open | Reference | |||||||
| Laparoscopy | 0.8 | 0.48 | 1.36 | 0.416 | ||||
| Conversion | 1.14 | 0.48 | 2.69 | 0.772 | ||||
| Anemia | 0.85 | 0.53 | 1.37 | 0.504 | ||||
| Albumin | ||||||||
| Normal | Reference | |||||||
| Hypoalbuminemia | 0.99 | 0.58 | 1.68 | 0.963 | ||||
| RBC transfusion | ||||||||
| Preoperative | 1.08 | 0.52 | 2.25 | 0.842 | ||||
| Intraoperative | 1.9 | 1.02 | 3.56 | 0.045 | ||||
| Stage | < 0.001 | |||||||
| 0,1 | Reference | |||||||
| 2 | 2.73 | 1.12 | 6.64 | 0.027 | ||||
| 3 | 5.74 | 2.43 | 13.56 | < 0.001 | ||||
| T stage | ||||||||
| Tis −2 | Reference | Reference | ||||||
| 3,4 | 3.94 | 1.81 | 8.6 | 0.001 | 3.06 | 1.17 | 8 | 0.023 |
| N stage | < 0.001 | 0.164 | ||||||
| 0 | Reference | |||||||
| 1 | 2.45 | 1.44 | 4.18 | 0.001 | 1.71 | 0.91 | 3.2 | 0.093 |
| 2 | 3.38 | 1.89 | 6.05 | < 0.001 | 1.8 | 0.89 | 3.66 | 0.105 |
| Lymphatic invasion | 1.86 | 1.17 | 2.98 | 0.009 | ||||
| Venous invasion | 2.54 | 1.45 | 4.48 | 0.001 | ||||
| Perineural invasion | 3.24 | 2 | 5.27 | < 0.001 | 2.08 | 1.18 | 3.66 | 0.011 |
| Differentiation | < 0.001 | 0.006 | ||||||
| Well | Reference | |||||||
| Moderate | 1.56 | 0.74 | 3.27 | 0.242 | 0.84 | 0.38 | 1.85 | 0.671 |
| Poor | 3.64 | 1.26 | 10.56 | 0.017 | 1.43 | 0.46 | 4.45 | 0.541 |
| Mucinous | 15.71 | 4.56 | 54.12 | < 0.001 | 10.99 | 2.85 | 42.35 | < 0.001 |
| Adjuvant Chemotherapy | 1.14 | 0.72 | 1.8 | 0.581 | ||||
| Chemotherapy completion | 0.85 | 0.44 | 1.61 | 0.606 | ||||
| Presarcopenia | 1.89 | 1.11 | 3.22 | 0.020 | ||||
ASA The American Society of Anesthesiologists (ASA) physical status, RBC Red blood cell, BMI Body mass index, NLR Neutrophil-to-lymphocyte ratio
Subgroup analysis
The Cox-regression test was conducted on patients with stage II high-risk colorectal cancer who underwent chemotherapy, examining the impact of chemotherapy on OS in both the presarcopenia and normal patient groups. Covariates included factors identified in previous analyses as influencing OS, such as pulmonary disease and ASA classification. Despite not reaching statistical significance, the analysis revealed that in the normal group, chemotherapy was associated with improved survival rates (HR 0.70, 95% CI 0.30–1.61, p = 0.396). In contrast, the presarcopenia group exhibited a trend suggesting that chemotherapy might decrease survival rates (HR 1.70, 95% CI 0.40–7.26, p = 0.475) (Fig. 4).
Fig. 4.
Survival function for overall survival in patients with stage II high-risk colorectal cancer between the nonpresarcopenia and presarcopenia
Although not statistically significant, the normal group showed a numerical trend toward benefit from adjuvant chemotherapy (HR 0.70, 95% CI 0.30–1.61, p = 0.396), whereas this trend was not observed in patients with presarcopenia (HR 1.70, 95% CI 0.40–7.26, p = 0.475).
Discussion
We observed that elderly patients with colorectal cancer and presarcopenia have poorer OS compared to those without presarcopenia. Additionally, the presence of presarcopenia during adjuvant chemotherapy was associated with a decrease in the frequency of completing chemotherapy. Particularly, among patients with high-risk stage II cancer, those with presarcopenia who underwent adjuvant chemotherapy tended to experience a further decline in OS rates.
Several indicators of sarcopenia have been reported, including skeletal muscle index (SMI), muscle attenuation, grip strength, and gait speed [13]. In the present study, we chose to use the psoas muscle index (PMI) as a surrogate marker of sarcopenia for several reasons. First, PMI can be readily measured from routine preoperative CT scans, which are commonly obtained in clinical practice [14], thus offering a practical and cost-effective approach. Second, PMI has been previously shown to be associated with postoperative outcomes and long-term prognosis, particularly in patients undergoing abdominal or colorectal surgery [15]. Lastly, compared to more comprehensive muscle measurements, PMI provides a relatively standardized and reproducible method with lower interobserver variability, especially when measured at the L3 vertebral level [16]. For these reasons, PMI was considered an appropriate and clinically relevant marker of sarcopenia in our study.
Our study exclusively focused on presarcopenia, as defined by the European Working Group on Sarcopenia in Older People (EWGSOP) [12]. In this study, patients were classified as having presarcopenia based on low skeletal muscle mass measured via the Psoas Muscle Index (PMI) on CT images. Due to the retrospective nature of the study, measurements of muscle strength or physical performance (e.g., handgrip strength or gait speed) were not available. Therefore, we adopted the term “presarcopenia” to describe patients with reduced muscle mass only. While the formal diagnosis of sarcopenia requires both low muscle mass and low muscle function according to EWGSOP [13] or AWGS criteria [17], we used presarcopenia as a surrogate concept that broadly includes individuals who may be considered sarcopenic had functional assessments been feasible. Due to ongoing debates surrounding the criteria for measuring muscle function in defining sarcopenia [18, 19], the majority of studies to date have defined sarcopenia based solely on loss of muscle mass. Li et al. reported in their 2023 study involving 939 patients with left-sided colon and rectal cancer that sarcopenia had an impact on OS, with a hazard ratio (HR) of 1.367 (95% CI: 1.049–1.782). Similarly, in a Japanese retrospective cohort study involving 310 patients, sarcopenia was reported to have a significant impact on OS with a HR of 2.270 (95% CI 1.147–4.494) [20]. Subsequently, findings from the C SCANS Study revealed that sarcopenia is associated with an HR of 1.28 (95% CI, 1.10–1.53) for OS [21].
In our study, elderly patients aged 75 years and older with presarcopenia showed higher NLR values, along with a higher frequency of anemia and hypoalbuminemia. A meta-analysis conducted in 2022 [22] explored the association of metabolic, hematologic, and inflammatory biomarkers with frailty and sarcopenia. The literature suggested that chronic inflammation may lead to frailty and sarcopenia, potentially leading to muscle catabolism and atrophy. In the context of chronic inflammation, the document indicated that hypoalbuminemia could occur due to decreased albumin synthesis in the liver, while anemia could result from reduced tissue oxygenation. Our study provides additional evidence supporting the claims made in the mentioned research.
There is ongoing debate regarding cancer treatment in elderly patients. Particularly for high-risk stage II colorectal cancer, some studies suggest that adjuvant chemotherapy may not contribute to improved survival rates [23, 24]. In our study, while we did not observe statistical significance when analyzing the impact of adjuvant chemotherapy on survival rates among stage II high-risk patients, there appeared to be a trend suggesting that chemotherapy contributed to improved survival rates in the overall patient population. However, in patients with presarcopenia, there was a trend indicating that chemotherapy might actually decrease survival rates. We observed a lower chemotherapy completion rate in presarcopenic patients, likely attributed to chemotherapy toxicity, consistent with previous literature findings [25]. It is speculated that the patients' may not have recovered their strength following the decline due to chemotherapy, potentially contributing to higher mortality. Further extensive research is needed to validate this hypothesis.
When interpreting our results, several analytical aspects merit consideration. Variables such as presarcopenia and pathological indicators of tumor invasion showed associations with survival outcomes at the univariate level; however, these relationships weakened or disappeared once clinically relevant factors were jointly accounted for in the multivariable framework. This pattern is plausibly attributable to the close interrelatedness of tumor pathological features, together with the relatively small number of outcome events, which necessitated a deliberately simplified modeling strategy to maintain estimate reliability. Notably, the relationship between presarcopenia and overall survival was observed consistently across both the primary prespecified analyses and complementary sensitivity analyses, suggesting that its association with overall survival is not dependent on a single modeling approach. By contrast, recurrence-free survival appeared to be largely explained by indicators of tumor extent, particularly pathological stage, rather than by patient-related characteristics such as presarcopenia.
The strength of our study lies, above all, in its focus on elderly patients with colorectal cancer, specifically investigating how presarcopenia impacts patient prognosis. Until now, evidence on application of treatment strategies based on the presence of presarcopenia in the treatment of elderly patients has been insufficient.
In our research findings, presarcopenia itself appeared to have no impact on recurrence, but it was identified as a factor influencing OS. Additionally, our study, which specifically targeted high-risk stage II patients who underwent adjuvant chemotherapy, confirmed that adjuvant chemotherapy did not contribute to improved OS rates in patients with presarcopenia. On the contrary, OS rates reduced further when adjuvant chemotherapy was administered in the presence of presarcopenia. However, given that these subgroup results were not statistically significant and the sample size was limited, the findings should be interpreted with caution. Therefore, confirming presarcopenia through CT in cases of high-risk stage II colorectal cancer could aid in deciding whether to proceed with adjuvant chemotherapy.
Although presarcopenia was not associated with increased recurrence in our study, it was linked to poorer overall survival. This discrepancy may be explained by the possibility that presarcopenia reflects overall frailty and reduced physiological reserve, leading to increased susceptibility to non-cancer-related mortality. Unfortunately, detailed cause-of-death data were not consistently available in this retrospective cohort, and this remains a limitation of our analysis.
Limitation
The first limitation of our study is that it is a retrospective cohort study, which may have introduced selection bias. In particular, the criteria for selecting chemotherapy were not clearly defined.
Second, the MSI status could not be included in the high-risk category in stage II cancer. Since the 2018 NCCN guidelines, routine MMR/MSI testing has been recommended for patients diagnosed with colorectal cancer. As our study population consists of patients diagnosed before 2018, we were unable to include this factor.
Third, our study did not include geriatric assessment. It is essential to choose individualized treatment methods through a comprehensive geriatric assessment, a diagnostic process that screens and confirms clinical health as well as physical and psychosocial impairments and functional disabilities [26].
Fourth, since not all patients were followed up for the full 5 years, the long-term survival estimates may be subject to bias. However, overall survival was assessed based on data from the National Cancer Center, a public institution that manages cancer survival statistics in Korea, rather than solely on follow-up at our institution. Therefore, we believe the results retain clinical significance.
Conclusion
Given the poorer overall survival observed in elderly colorectal cancer patients with presarcopenia, the benefit of adjuvant chemotherapy in this population remains uncertain and should be individualized. Future multi-center research, including a comprehensive geriatric assessment, is essential to address the limitations of our study.
Acknowledgements
The authors wish to acknowledge the financial support of the Catholic Medical Center Research Foundation made in the program year of 2023.
Authors’ contributions
Kil-yong Lee had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Kil-yong Lee, Jaeim Lee Acquisition, analysis, or interpretation of data: Kil-yong Lee, Jaeim Lee Drafting of the manuscript: Kil-yong Lee Critical revision of the manuscript for important intellectual content: Kil-yong Lee, Jaeim Lee, Seong Taek Oh Statistical analysis: Kil-yong Lee Administrative, technical, or material support: Jaeim Lee, Seong Taek Oh Supervision: Jaeim Lee, Seong Taek Oh.
Funding
Not applicable.
Data availability
The data from this study are available upon request owing to the restrictions (data contain potentially identifying information [birth dates]) imposed by our ethics committee (IRB). Please contact our IRB committee for data access via e-mail (irbujb@catholic.ac.kr).
Declarations
Ethics approval and consent to participate
This study was approved by the institutional review board (IRB) of the Catholic University of Korea and was performed in accordance with the IRB’s guidelines and regulations (UC21RISI0035). The requirement for informed consent was waived by the IRB of the Catholic University of Korea.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Larsson L, Degens H, Li M, Salviati L, Lee YI, Thompson W, et al. Sarcopenia: aging-related loss of muscle mass and function. Physiol Rev. 2019;99(1):427–511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Boirie Y. Physiopathological mechanism of sarcopenia. J Nutr Health Aging. 2009;13(8):717–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Keller K. Sarcopenia. Wien Med Wochenschr. 2019;169(7–8):157–72. [DOI] [PubMed] [Google Scholar]
- 4.Smith L, Tully M, Jacob L, Blackburn N, Adlakha D, Caserotti P, et al. The Association Between Sedentary Behavior and Sarcopenia Among Adults Aged >/=65 Years in Low- and Middle-Income Countries. Int J Environ Res Public Health. 2020;17(5). [DOI] [PMC free article] [PubMed]
- 5.Laviano A. Sarcopenia, biological age and treatment eligibility in patients with cancer. Curr Opin Clin Nutr Metab Care. 2023;26(1):59–63. [DOI] [PubMed] [Google Scholar]
- 6.Lee CS, Won DD, Oh SN, Lee YS, Lee IK, Kim IH, et al. Prognostic role of pre-sarcopenia and body composition with long-term outcomes in obstructive colorectal cancer: a retrospective cohort study. World J Surg Oncol. 2020;18(1):230. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Sakai M, Sohda M, Saito H, Ubukata Y, Nakazawa N, Kuriyama K, et al. Impact of combined assessment of systemic inflammation and presarcopenia on survival for surgically resected esophageal cancer. Am J Surg. 2021;221(1):149–54. [DOI] [PubMed] [Google Scholar]
- 8.Song JH, Oh RK, Lee JE, Lee KH, Kim JY, Kim JS. Computed tomography-assessed presarcopenia and clinical outcomes after laparoscopic surgery for rectal cancer. Ann Coloproctol. 2023;39(6):513–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Takada H, Amemiya F, Yasumura T, Yoda H, Okuwaki T, Imagawa N, et al. Relationship between presarcopenia and event occurrence in patients with primary hepatocellular carcinoma. Sci Rep. 2020;10(1):10186. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Yancik R, Wesley MN, Ries LA, Havlik RJ, Long S, Edwards BK, et al. Comorbidity and age as predictors of risk for early mortality of male and female colon carcinoma patients: a population-based study. Cancer. 1998;82(11):2123–34. [PubMed] [Google Scholar]
- 11.Hiraoka A, Aibiki T, Okudaira T, Toshimori A, Kawamura T, Nakahara H, et al. Muscle atrophy as pre-sarcopenia in Japanese patients with chronic liver disease: computed tomography is useful for evaluation. J Gastroenterol. 2015;50(12):1206–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010;39(4):412–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyere O, Cederholm T, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019;48(1):16–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Jones K, Gordon-Weeks A, Coleman C, Silva M. Radiologically determined sarcopenia predicts morbidity and mortality following abdominal surgery: a systematic review and meta-analysis. World J Surg. 2017;41(9):2266–79. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Batista A, Petty D, Fairhurst C, Davies S. Psoas muscle mass index as a predictor of long-term mortality and severity of complications after major intra-abdominal colorectal surgery - a retrospective analysis. J Clin Anesth. 2023;84:110995. [DOI] [PubMed] [Google Scholar]
- 16.Hamaguchi Y, Kaido T, Okumura S, Kobayashi A, Hammad A, Tamai Y, et al. Proposal for new diagnostic criteria for low skeletal muscle mass based on computed tomography imaging in Asian adults. Nutrition. 2016;32(11–12):1200–5. [DOI] [PubMed] [Google Scholar]
- 17.Chen LK, Woo J, Assantachai P, Auyeung TW, Chou MY, Iijima K, et al. Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment. J Am Med Dir Assoc. 2020;21(3):300-7 e2. [DOI] [PubMed]
- 18.Carvalho do Nascimento PR, Bilodeau M, Poitras S. How do we define and measure sarcopenia? A meta-analysis of observational studies. Age Ageing. 2021;50(6):1906–13. [DOI] [PubMed] [Google Scholar]
- 19.Fox B, Henwood T, Schaap L, Bruyere O, Reginster JY, Beaudart C, et al. Adherence to a standardized protocol for measuring grip strength and appropriate cut-off values in adults over 65 years with sarcopenia: a systematic review protocol. JBI Database System Rev Implement Rep. 2015;13(10):50–9. [DOI] [PubMed] [Google Scholar]
- 20.Miyamoto Y, Baba Y, Sakamoto Y, Ohuchi M, Tokunaga R, Kurashige J, et al. Sarcopenia is a negative prognostic factor after curative resection of colorectal cancer. Ann Surg Oncol. 2015;22(8):2663–8. [DOI] [PubMed] [Google Scholar]
- 21.Feliciano EMC, Kroenke CH, Meyerhardt JA, Prado CM, Bradshaw PT, Kwan ML, et al. Association of systemic inflammation and sarcopenia with survival in nonmetastatic colorectal cancer: results from the C SCANS study. JAMA Oncol. 2017;3(12):e172319. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Picca A, Coelho-Junior HJ, Calvani R, Marzetti E, Vetrano DL. Biomarkers shared by frailty and sarcopenia in older adults: a systematic review and meta-analysis. Ageing Res Rev. 2022;73:101530. [DOI] [PubMed] [Google Scholar]
- 23.Lee KY, Park JW, Lee KY, Cho S, Kwon YH, Kim MJ, et al. Adjuvant chemotherapy does not provide survival benefits to elderly patients with stage II colon cancer. Sci Rep. 2019;9(1):11846. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Lee Y, Park I, Cho H, Gwak G, Yang K, Bae BN. Effect of adjuvant chemotherapy on elderly stage II high-risk colorectal cancer patients. Ann Coloproctol. 2021;37(5):298–305. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Gerard S, Brechemier D, Lefort A, Lozano S, Abellan Van Kan G, Filleron T, et al. Body Composition and Anti-Neoplastic Treatment in Adult and Older Subjects - A Systematic Review. J Nutr Health Aging. 2016;20(8):878-88. [DOI] [PMC free article] [PubMed]
- 26.Roh YK. Comprehensive geriatric assessment for the evaluation of the health statuses of elderly patients. J Korean Med Assoc. 2023;66(7):439–47. [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data from this study are available upon request owing to the restrictions (data contain potentially identifying information [birth dates]) imposed by our ethics committee (IRB). Please contact our IRB committee for data access via e-mail (irbujb@catholic.ac.kr).