Predictors of changes in skeletal muscle mass after esophagectomy in elderly patients with esophageal cancer

Purpose : Although a change in skeletal muscle mass index (SMI) 4 months after esophagectomy impacts prognosis, predictors of a change in SMI have not been revealed. The purpose of this exploratory retrospective study was to clarify the predictors of a change in SMI after curative esophagectomy in elderly patients with esophageal cancer. Methods : Fifty-four patients who underwent esophagectomy and perioperative rehabilitation from 2015 to 2018 were enrolled. Preoperative and postoperative SMI (cm 2 /m 2 ) were calculated using computed tomography images. The ratio change in SMI was calculated as follows: (postoperative SMI − preoperative SMI) ÷ preoperative SMI × 100%. Potential predictors of a change in SMI ratio were analyzed by multiple regression. Results : The mean ratio change in SMI 4 months after esophagectomy was −7.1% ± 9.4%. The ratio change in quadriceps muscle strength in the rst month after surgery ([postoperative strength − preoperative strength] ÷ preoperative strength × 100%) (standardized β = .273, p = .038) and neoadjuvant chemotherapy (NAC) (standardized β = .398, p = .006) were predictors of the ratio change in SMI independent of age, sex, pathological stage, and preoperative SMI. Conclusion : Quadriceps muscle weakness in the rst month after esophagectomy and NAC were predictors of the ratio change in SMI after esophagectomy. Continuous postoperative comprehensive rehabilitation and supportive care may inhibit loss of skeletal muscle mass. Multiple regression was used for the multivariate analysis of ratio change in SMI in 54 patients who underwent esophagectomy. Multiple regression was performed with potential predictors detected by a univariate analysis and confounding factors. The above categorical variables were analyzed as and


Introduction
The 5-year survival rates of patients with clinical stage II and III esophageal cancer (Union for International Cancer Control tumor-node-metastasis [UICC-TNM] classi cation, 6 th edition) after esophagectomy are approximately 65% and 40% [1], respectively. This type of cancer has a poor prognosis compared with other cancers. The number of elderly patients with esophageal cancer (aged over 70 years) is increasing, and these patients have a poor prognosis after esophagectomy [2][3][4][5].
Skeletal muscle mass at pretreatment is an important factor for prognosis in elderly patients with solid tumors, including esophageal cancer [6,7]. In patients with esophageal cancer, a change in skeletal muscle mass index (SMI) within 6 months after esophagectomy is an important factor for overall survival, independent of pretreatment SMI [4,8,9]. A change in skeletal muscle mass is generally associated with four factors: aging, disease, physical function, and nutrition [10][11][12][13][14]. In fact, previous studies reveal that patients with advanced pathological tumor stage and abundant preoperative SMI have a marked loss of skeletal muscle mass 4 months after esophagectomy [4,9]. However, no studies have investigated the impact of reversible factors, such as physical function and nutrition, on the change in skeletal muscle mass in elderly patients with esophageal cancer after esophagectomy. If reversible factors, such as physical function and nutrition, are predictors of postoperative changes in skeletal muscle mass in elderly patients with esophageal cancer, appropriate rehabilitation, including exercise and nutrition, may prevent critical loss of skeletal muscle mass and improve prognosis after esophagectomy.
This study aimed to clarify predictors of a change in skeletal muscle mass after curative esophagectomy in elderly patients with esophageal cancer, including indicators of physical function and nutrition.

Design and participants
This study was a retrospective cohort study. Subjects were over 70 years of age and had undergone curative esophagectomy for esophageal cancer at the National Cancer Center East Hospital between September 2015 and December 2018. The inclusion criteria were as follows: 1) completion of physical function and nutritional assessments; 2) computed tomography (CT) within 2 months prior to and 4 ± 2 months after esophagectomy. The exclusion criteria were as follows: 1) readmission, death, or recurrence by the day of postoperative CT; 2) distant metastasis at esophagectomy; 3) untreated or undertreated duplicate cancer; 4) missing data. Informed consent was obtained through an opt-out consent process due to the retrospective nature of the study. This study was approved by the research ethics committee of the National Cancer Center (2019-075) in accordance with the Declaration of Helsinki.

Perioperative rehabilitation
Perioperative rehabilitation was performed on all subjects. Preoperative rehabilitation is a home-based intervention, consisting of respiratory training with incentive spirometry; resistance training, such as squats and heel-lift exercises; and aerobic exercise with walking. Postoperative rehabilitation was performed from the rst postoperative day at an intensive care unit up until discharge for 20-40 minutes per day, including early mobilization, respiratory training, resistance training, and aerobic exercise depending on the individual's condition.

Physical function and nutrition
Preoperative and postoperative physical function, including isometric quadriceps muscle strength (QS) (IsoForce GT-330, OG GIKEN, Japan) [19], usual gait speed of 4 meters [20], preoperative and postoperative nutrition (prognostic nutrition index [PNI] [21]), and body mass index (BMI), were collected from medical records. For isometric QS, the side with a greater muscle strength was analyzed. Physical function and nutrition were measured within 3 months before esophagectomy and at the rst visit after discharge (within the rst month after discharge). In the variables of physical function and nutrition, the change ratio (%) after esophagectomy was calculated as follows: (postoperative value − preoperative value) ÷ preoperative value × 100%.

Ratio change in SMI
We used SMI [24], which was calculated from CT images at the level of L3, as an indicator of skeletal muscle mass. CT was performed twice within 3 months prior to and 4 ± 2 months after esophagectomy.

Statistics
Descriptive statistics are presented as number of people and mean ± standard deviation. The difference in SMI before, compared with after, esophagectomy was analyzed with a paired t-test. With a univariate analysis, associations between the ratio change in SMI and physical function, nutrition, and patient characteristics were analyzed with simple linear regression. Multiple regression was performed using the forced entry method. The dependent variable was the ratio change in SMI. Explanatory variables were potential predictors of a ratio change in SMI with signi cance in a univariate analysis. Confounding variables were age, sex, preoperative SMI [9], and pStage [4]. A strati ed analysis for SMI was performed using these predictors. Patients were divided into two groups with a median value as a cut-off point if the predictor was a continuous variable. Differences in preoperative and postoperative SMI between the two groups were compared with one-way analysis of variance adjusted using the Bonferroni method. Then, the association of predictors with other factors was analyzed using logistic regression. Statistical signi cance was considered as a two-tailed p value of <0.05. All analyses were performed with SPSS version 26 (IBM Corp., Japan) for Windows. Linear regression was drawn using R version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria).

Patient characteristics
A total of 54 patients were analyzed ( Figure 1). The mean age was 75.3 ± 3.6 years, and the number of males was 42 (78%). There was a signi cant difference between preoperative SMI (40.3 ± 7.7 cm 2 /m 2 ) and postoperative SMI (37.3 ± 7.4 cm 2 /m 2 ) (p < 0.001). The mean ratio change in SMI was −7.1% ± 9.4% (Table 1). Regarding the timing of assessments, the mean number of months of preoperative and postoperative CT scans were 1.3 ± 0.6 months before and 4.1 ± 0.6 months after esophagectomy. The mean days of preoperative and postoperative physical function and BMI were 4.9 ± 7.5 days before and 36.4 ± 12.8 days after esophagectomy. The mean days of preoperative and postoperative PNI were 3.6 ± 2.8 days before and 33.9 ± 9.3 days after esophagectomy.

Predictors of a change in SMI
Multiple regression analysis showed that the ratio change in QS in the rst month after esophagectomy (standardized β = 0.274, p = 0.038) and NAC (standardized β = 0.387, p = 0.008) was a predictor of the ratio change in SMI, independent of sex, age, preoperative SMI, and pStage ( Figure 2, Table 2). The coe cient of determination (R 2 ) of the model was 0.26. With a strati ed analysis, patients with a marked decline in QS tended to have a lower SMI 4 months after esophagectomy, compared with patients with less of a decline. We de ned the median value (−9.9%) as the cut-off point (36.3 ± 8.0 cm 2 /m 2 vs. 38.4 ± 6.8 cm 2 /m 2 , Figure 3). There was a signi cant difference between patients treated with NAC versus those treated without NAC in preoperative SMI (Figure 3). In addition, patients treated with NAC tended to have a lower SMI 4 months after esophagectomy, compared with patients treated without NAC (36.4 ± 7.7 cm 2 /m 2 vs. 38.4 ± 7.1 cm 2 /m 2 , Figure 3b).

Discussion
The present study investigated predictors of a change in skeletal muscle mass after curative esophagectomy in 54 elderly patients with esophageal cancer aged over 70 years. The mean ratio change in SMI 4 months after esophagectomy was −7.1% ± 9.4%. From the multiple regression analysis, a change in QS in the rst month after esophagectomy and NAC were predictors for a change in SMI 4 months after esophagectomy.
A decline in isometric QS in the rst month after esophagectomy was a signi cant predictor for loss of SMI 4 months after esophagectomy (Table 2, Figure 2). Previous large cohort studies report that a change in muscle strength precedes a change in skeletal muscle mass in community-dwelling older adults [13,14]. Our results in elderly patients with esophageal cancer support these previous studies.
Regarding recovery of QS after esophagectomy, QS signi cantly improved from the rst month to 3 months after surgery in patients with esophageal cancer [24]. Therefore, due to diversity in QS recovery after esophagectomy, changes in QS in the rst month after esophagectomy may be predictive of a decrease in SMI 4 months after surgery.
Moreover, a decline in QS in the rst month after esophagectomy was associated with a decline in usual gait speed and a long length of hospital stay in our study (Table 3). Previous studies have shown that QS and gait speed are associated with physical activity [25,26]. Hence, the change in QS in the rst month after esophagectomy may be impacted by physical activity [27][28][29] before and after discharge. In addition, because physical function is impacted by postoperative complications [24] and physical symptoms [30], a decline in QS may be associated with a long length of hospital stay. Therefore, continuous rehabilitation combined with perioperative supportive care for improving physical activity, preventing complications, and inhibiting symptoms may improve prognosis by preventing loss of skeletal muscle mass in elderly patients with esophageal cancer.
In our study, NAC was a signi cant predictor for less marked loss of SMI 4 months after esophagectomy. Patients treated with NAC were signi cantly associated with a lower preoperative SMI and BMI (Table 3) and had a signi cantly lower preoperative SMI compared with patients who did not receive NAC (Figure 3). NAC reduced skeletal muscle mass by approximately 3% because of side effects, such as fatigue, loss of appetite, and decreased exercise tolerance accompanied by thrombocytopenia [31][32][33][34][35]. It has also been revealed that patients with a low preoperative SMI have less marked loss of SMI after esophagectomy [9]. Therefore, less marked loss of SMI after esophagectomy in patients treated with NAC may be attributed to a decrease in SMI during NAC.
Meanwhile, nutritional factors were not predictors for a change in SMI after surgery. In addition, unlike previous studies, progression of tumors was not a signi cant predictor of a change in SMI after esophagectomy in the present study. This may be because SMI in vulnerable elderly patients may be in uenced by factors such as physical function and cognitive and social function compared with younger patients [36,37]. Regarding nutritional factors, we were not able to evaluate actual dietary intake and appetite. Stronger predictive indicators of a change in SMI may have been included in our analysis. Second, the statistical power was low because of the small sample size in the present study. Therefore, the impact of tumor progression and nutrition on changes in SMI in elderly patients after esophagectomy may be poor in the present study.
There are several limitations to the present study. First, causal relationships between outcomes and predictors were not guaranteed due to the retrospective observational nature of the study. Second, it is necessary to verify external validity due to the small sample size and the fact that the study was conducted at a single institution. Third, potential predictors that had a strong impact may not have been included in the analysis. We were not able to assess the amount of physical activity, dietary intake, and cognitive and social function owing to the retrospective nature of the study. Furthermore, the coe cient of determination (R 2 ) for the multiple regression analysis was 0.26, which indicated that the t of the model was poor. In light of these limitations, we have to interpret the results carefully.

Conclusion
In the present study, we clari ed predictors of a change in SMI in 54 elderly patients aged over 70 years with esophageal cancer after esophagectomy. Multiple regression showed that the independent predictors of a change in SMI 4 months after esophagectomy were a ratio change in isometric QS in the rst month after esophagectomy and NAC. Supportive care and continuous comprehensive rehabilitation after esophagectomy might prevent loss of skeletal muscle mass after esophagectomy in elderly patients with esophageal cancer.

Declarations [Acknowledgments]
The authors thank the members of the Department of Musculoskeletal Oncology and Rehabilitation, Esophageal Surgery, for their support; this research would not have been possible without their cooperation. We thank Emily Woodhouse, PhD, from Edanz Group (https://en-authorservices.edanz.com/ac) for editing a draft of this manuscript. [Funding] Nothing.

[Con icts of interest]
The authors declare no potential con icts of interest with regard to the research, authorship, or publication of this article.

[Ethics Approval]
This study was approved by the research ethics committee of the National Cancer Center (2019-075) in accordance with the Declaration of Helsinki.
[Consent to participate] Informed consent was obtained through an opt-out consent process.
[Consent for publication (include appropriate statements) ] Not applicable.
[Availability of data and materials] The participants of this study did not agree for their data to be shared publicly. The data of participants is not available.