Pre-Operative Resistance Training and Amino Acid Supplementation in Frail Patients with Gastrointestinal Cancer: A Randomized Clinical Trial

doi:10.21203/rs.3.rs-5257948/v1

Background

Preoperative frailty is a risk factor for postoperative complications and poor prognosis in older patients. We aimed to investigate the impact of preoperative exercise and nutritional interventions on the frequency of postoperative complications, physical function, and activities of daily living (ADL) one year postoperatively in frail older patients with gastrointestinal cancer.

Methods

This single-center, randomized controlled trial included 62 patients aged ≥ 70 years who were scheduled for elective surgery for gastrointestinal cancer with decreased grip strength or walking speed between October 2017 and December 2022. The participants were randomly assigned to the control (n = 33) and intervention (n = 29) groups. Participants in the intervention group performed resistance exercises and consumed amino acid-containing jelly daily at home for 14 days. All participants were followed up for one year. Variables were compared using the two-sided Student's t-test or Fisher's exact test. Statistical significance was set at p < 0.05.

Results

After exclusion, 45 patients were included in the analysis, with 27 and 18 in the control and intervention groups, respectively. The average age was 80.4 years, and 37.8% of the participants were male. Postoperative complications were observed in 48.1% and 44.4% of the control and intervention groups, respectively (95% confidence interval (CI) 0.57–2.07). Postoperative delirium was observed in 25.9% and 33.3% of the control and intervention groups, respectively (95% CI 0.31–1.94). No significant differences were observed between the two groups in grip strength, walking speed, and skeletal muscle index during follow-up. However, knee extension strength was better maintained in the intervention group at discharge (preoperatively: 100.2 ± 18.3% vs 119.1 ± 68.8%, p = 0.19; discharge: 86.7 ± 22.0% vs 119.3 ± 72.0%, p = 0.044). The proportion of patients with decreased ADL or death was lower in the intervention group than in the control group one year postoperatively (42.3% vs 23.5%; RR 0.56, 95% CI 0.08–1.92).

Conclusions

A 14-day preoperative exercise and nutritional intervention program did not significantly reduce the frequency of postoperative complications in frail older patients with gastrointestinal cancer. However, it aided in maintaining knee extension strength at discharge.

Trial Registration:

UMIN (University Hospital Medical Information Network) Clinical Trials Registry (ID: UMIN000024526), registered on 1 December 2016.

Preoperative frailty

preoperative exercise

amino acids

gastrointestinal cancer

The number of older patients with gastrointestinal cancer is rising with the increasing proportion of aging within the general population.[1] Frailty is a multifaceted syndrome characterized by decreased physical function, malnutrition, cognitive impairment, psychological health deterioration, and social instability, which increases the risk of mortality, hospitalization, and falls under stress.[2–4] The prevalence of frailty in patients with cancer is higher than that in the general population.[5] The decline in the quality of life (QOL) in patients with cancer is influenced by the stage of the disease, treatment, weight loss, and loss of appetite.[6, 7] In particular, patients with gastrointestinal cancer often suffer from malnutrition due to obstruction or absorption disorders at the time of diagnosis.[8] The incidence of postoperative complications is higher in patients with frailty, which negatively affects their survival rate.[9–11] Assessing frailty before surgery is imperative for predicting postoperative complications. Our research group previously reported that overall health status assessed using comprehensive geriatric assessment (CGA) was associated with postoperative delirium, independent of the progression of gastrointestinal cancer,[12] and decreased physical function was related to the risk of postoperative mortality in gastrointestinal cancer surgery.[13] Combining CGA with cancer assessments can clarify the risk of postoperative mortality.[14]

Frailty is a complex condition observed in older adults characterized by the interaction and progression of multiple factors including decreased physical function, malnutrition, and social isolation.[15] This vicious cycle is known as the frailty cycle that significantly affects the health and QOL of older adults.[16] Interventions for frailty should combine multiple approaches such as physical rehabilitation, social support, nutritional therapy, and cognitive training for the greatest effectiveness.[17, 18] Therefore, this study examined the effects of combined exercise and nutritional interventions in patients with decreased physical function.

Decreased physical function leads to reduced activity and dietary intake, whereas malnutrition reduces skeletal muscle mass and physical function. In contrast, low skeletal muscle mass is associated with insulin resistance, inflammation, and adverse drug events,[19, 20] which increases the frequency of postoperative complications.[21, 22] Maintaining skeletal muscle function and improving nutritional status can reduce the progression of frailty due to the stress of surgery, thereby reducing postoperative complications and risk of mortality while preventing a decline in activities of daily living (ADL). Exercise therapy can increase muscle strength and mass in older adults,[23, 24] as well as improve insulin resistance,[25] which aids in reducing postoperative complications and improves prognosis. Amino acids, particularly leucine, activate the mammalian target of rapamycin signaling pathway[26, 27] and promote the synthesis of muscle protein, thereby contributing to the maintenance and increase in muscle mass and strength, as well as improving insulin resistance.[28, 29] Therefore, the supplementation of amino acids such as leucine may play an important role in maintaining or improving skeletal muscle function in older patients during the perioperative period.

This study aimed to investigate the impact of combined resistance exercise and supplementing amino acids on perioperative physical function, the frequency of postoperative complications, and one-year prognosis in older patients with gastrointestinal cancer with decreased physical function.

Ethics

This study was approved by the Clinical Research Committee (Ethics Review Number 16124-4) and was registered with the University Hospital Medical Information Network (UMIN), Japan (UMIN000024526). This study was conducted in accordance with the Declaration of Helsinki of 1964 and its later amendments or comparable ethical standards. Written informed consent was obtained from all participants, and all participants were assured of their right to withdraw consent.

Design

This was a single-center, open-label, prospective, randomized controlled trial, following the consolidated standards of reporting Trials (CONSORT) reporting guidelines.[30]

Participants

Patients aged ≥ 70 years scheduled for elective gastrointestinal cancer surgery at the University Hospital were recruited between October 2017 and December 2022. The inclusion criteria were patients who showed decreased grip strength or walking speed in the preoperative evaluations and agreed to participate in the study. Decreased grip strength was defined as grip strength < 26 kg in men and < 18 kg in women, whereas decreased walking speed was defined as walking speed < 1.0 m/s. The exclusion criteria were patients with exertional angina, chronic heart failure (New York Heart Association [NYHA] classification II or higher), tachyarrhythmia, chronic respiratory failure (Hugh-Jones classification II or higher), active multiple cancers, chronic renal failure (estimated glomerular filtration rate < 30 mL/min/1.73 m²), severe liver dysfunction (aspartate transferase or alanine transaminase > 100 IU/L), and cognitive impairment (Mini-Mental State Examination (MMSE) < 20 points); undergoing preoperative chemotherapy; and unable to walk independently; as well as those participating in other clinical trials.

Randomization

Randomization was performed using Research Electronic Data Capture (REDCap), which was developed by Vanderbilt University and used under a licensing agreement with the University. Eligibility and inclusion were determined by the staff conducting the preoperative evaluation. Participants were randomly assigned to the control and intervention group in a 1:1 ratio and stratified by age, MMSE score, and Geriatric Depression Scale-15 (GDS-15) using REDCap, which provided an independent and automated allocation concealment mechanism. The allocation sequence was concealed until the participants were assigned to their respective groups. The participants were not blinded.

Interventions

The participants in the intervention group performed resistance exercises and consumed amino acid-containing jelly daily at home for 14 days. The resistance exercises constituted four types of bodyweight training (20 seated knee extensions, 20 standing thigh lifts, 10 standing calf raises, and 5–10 squats), which were performed twice daily. Compliance was confirmed by self-recording in a training log. The amino acid-containing jelly (©Amino L40) included 40% leucine and was consumed once daily. Both groups wore an activity tracker for two weeks.

Assessments

Assessments were conducted two weeks preoperatively, immediately preoperatively, at discharge, and one year postoperatively. The primary endpoint was the occurrence of postoperative complications including delirium. Secondary endpoints included changes in physical function over time and death or a decline in ADL one year postoperatively. The presence of postoperative complications was determined by reviewing medical records postoperatively by a physician blinded to the group assignments. The CGA and physical function evaluations were conducted as described previously.[13] The CGA includes the Barthel Index (ADL), Lawton's Instrumental Activities of Daily Living (IADL), MMSE,[31] Vitality Index, GDS-15, and Apathy Scale.[32] Physical function evaluations included isometric knee extension strength, grip strength, walking speed, and skeletal muscle mass index (SMI). Knee extension strength was measured five times on each side using a handheld dynamometer (μ-tas F-1, Anima Co., Ltd.), and the average value was recorded. Grip strength was measured three times on each side, and the average value was recorded (Toei Light Co., Ltd.). Walking speed and SMI (measured using an MC-190; Tanita Corporation) were also recorded. Changes in grip strength, knee extension strength, walking speed, and SMI over time were calculated as percentages of the baseline values at two weeks preoperatively. Cancer-related information, including disease name, stage, surgical procedure, and performance status (PS), was obtained as described previously,[14] and blood test results were obtained from electronic medical records. Frailty was assessed using the Japanese version of the Cardiovascular Health Study (J-CHS) criteria.[33] Daily steps and energy expenditure were recorded using a three-axis accelerometer (Mediwalk® MT-KT02DZ, Terumo, Tokyo, Japan). The compliance rates for wearing the activity tracker and for resistance exercises were calculated based on the number of days the tracker was worn and the number of completed exercises out of the prescribed number, respectively. A one-year postoperative follow-up was conducted using electronic medical records.

Statistical Analysis

All statistical analyses were performed using EZR[34] version 1.61 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R version 4.2.2 (The R Foundation for Statistical Computing, Vienna, Austria). This is a modified version of the R commander designed to add statistical functions and is frequently used in biostatistics.

The required sample size was calculated to be 92, assuming a postoperative complication rate of 50% in frail patients and expecting a reduction to 20% with the interventions, with an α error of 0.05, a β error of 0.20, and a power of 0.80. We planned to enroll 100 participants to account for dropouts. However, conducting the interventions within the scheduled period before surgery proved difficult, and the recruitment process was further affected by the COVID-19 pandemic, causing challenges in recruiting participants. Consequently, we decided to stop recruitment after 53 months, without achieving the initially planned number of participants.

Continuous variables were compared using the two-sided Student's t-test, whereas categorical variables were compared using the two-sided Fisher's exact test. Statistical significance was set at p <0.05.

Participants

The flowchart of the participants is shown in Figure 1. Consent was obtained from 62 individuals, of whom 17 were excluded from the analysis for the following reasons: five withdrew consent, six had changes in treatment plans, five could not follow the protocol due to changes in surgical schedules, and one was found to have multiple cancers. In total, 45 patients were included in the analysis, with 27 and 18 in the control and intervention groups, respectively. The average age was 80.4 years, and 37.8% of the participants were male. Survival data were available for all participants at the one-year follow-up; however, one participant from each group could not be evaluated by the assessors. The postoperative diagnoses included esophageal, gastric, gastrointestinal stromal, duodenal, liver, metastatic liver, bile duct, pancreatic, colon, and cecal cancers. No adverse or side effects related to the intervention were reported.

Baseline Characteristics

The baseline characteristics are shown in Table 1. No significant differences were observed in age, sex, and body mass index (BMI) between the control and intervention groups. The types of cancer, clinical stages of cancer, surgical methods, and performance statuses were also similar between the two groups. There were no significant differences in components of the CGA, including the Barthel Index, Lawton's IADL, MMSE, Vitality Index, GDS-15, and Apathy Scale. The results of physical function evaluations, including grip strength, isometric knee extension strength, walking speed, and SMI, also showed no significant differences. The serological evaluation revealed no significant differences in hemoglobin, serum albumin, serum creatinine, and serum C-reactive protein values between the two groups.

Table 1. Baseline characteristics

Variable	Control Group (n=27)	Intervention Group (n=18)	P-value
Age (years)	80.6 ± 5.4	80.0 ± 3.4	0.68
Sex (male, n %)	9 (33.3%)	8 (44.4%)	0.54
BMI (kg/m²)	22.0 ± 3.3	21.6 ± 5.3	0.78
Cancer Type (%)			0.27
- Upper gastrointestinal	6 (22.2%)	3 (16.7%)
- Hepatobiliary pancreas	8 (29.6%)	10 (55.6%)
- Lower gastrointestinal	13 (48.1%)	5 (27.8%)
Clinical Stage (%)			0.47
- 0-1	10 (37.0%)	6 (33.3%)
- 2	10 (37.0%)	7 (38.9%)
- 3	4 (14.8%)	2 (11.1%)
- 4	3 (11.1%)	3 (16.7%)
Surgery Method (%)			0.09
- Open surgery	7 (25.9%)	9 (50.0%)
- Laparoscopic surgery	20 (74.1%)	9 (50.0%)
Preoperative Chemotherapy (yes, %)	1 (3.7%)	1 (5.6%)	1.00
Performance Status (%)			1.00
- 0	23 (85.2%)	17 (94.4%)
- 1	2 (7.4%)	1 (5.6%)
- 2	1 (3.7%)	0 (0.0%)
- 3	1 (3.7%)	0 (0.0%)
Comprehensive Geriatric Assessment
- MMSE	26.1 ± 2.3	25.9 ± 2.1	0.82
- Barthel index	96.9 ± 7.9	98.1 ± 3.5	0.55
- IADL (Lawton's scale)	6.2 ± 2.2	6.7 ± 1.4	0.46
- Vitality index	9.8 ± 0.7	10.0 ± 0.0	0.26
- GDS-15	2.7 ± 3.0	3.2 ± 2.7	0.63
- Apathy scale	10.7 ± 6.1	9.9 ± 5.6	0.66
Total Number of Medications	6.1 ± 2.9	4.9 ± 2.8	0.18
Grip Strength (kg) Men	21.9 ± 4.3	24.5 ± 5.6	0.29
Grip Strength (kg) Women	15.8 ± 1.9	15.5 ± 3.2	0.74
Isometric Knee Extension Strength (kg)
- Men	21.8 ± 7.0	25.5 ± 7.3	0.30
- Women	17.0 ± 4.6	14.7 ± 5.7	0.24
Walking Speed (m/s)	1.1 ± 0.2	1.0 ± 0.3	0.72
SMI (kg/m²) Men	7.2 ± 1.0	6.8 ± 1.2	0.43
SMI (kg/m²) Women	6.0 ± 0.6	6.0 ± 1.0	0.96
J-CHS Criteria Frailty			0.76
- Prefrail	14 (51.9%)	11 (61.1%)
- Frail	13 (48.1%)	7 (38.9%)
Hemoglobin (g/dL)	11.6 ± 2.2	12.7 ± 1.9	0.11
Serum Albumin (g/dL)	3.8 ± 0.4	3.9 ± 0.4	0.57
Serum Creatinine (mg/dL)	0.86 ± 0.26	0.81 ± 0.31	0.55
CRP (mg/dL)	0.84 ± 2.4	0.94 ± 1.47	0.87

Baseline characteristics of participants in the control and intervention groups. Continuous variables are expressed as mean ± SD and were compared using Student's t-test. Categorical variables are expressed as counts and percentages and were compared using Fisher's exact test. P-values indicate statistical significance between groups.

BMI: body mass index; SMI: skeletal muscle mass index; CRP: C-reactive protein. IADL: Lawton's Instrumental Activities of Daily Living; MMSE: Mini Mental Status examination; GDS-15, Geriatric Depression Scale-15; J-CHS, the Japanese version of the Cardiovascular Health Study.

[Table 1 here]

Adherence to Exercise

The rates of adherence to exercise are shown in Table 2. The compliance rate for wearing the activity tracker was 98.0% and 96.4% in the control and intervention groups, respectively, with participants wearing the activity tracker for nearly the entire two-week pre-surgery period (p=0.45). Only participants in the intervention group performed resistance training, with an average rate of adherence to exercise of 85.2%.

Table 2. Adherence to exercise and physical activity in the control and intervention groups

Variable	Control Group (n=27)	Intervention Group (n=18)	P-value
Activity Tracker Compliance (%)	98.0 ± 6.1	96.4 ± 7.9	0.45
Exercise Adherence Rate (%)	N/A	85.2 ± 20.0	N/A
Daily Steps (steps/day)	4045.9 ± 2161.6	3816.9 ± 2142.2	0.73
Total Daily Energy Expenditure (kcal/day)	1511.7 ± 250.0	1491.7 ± 226.0	0.79

Continuous variables are presented as mean ± SD and were compared using Student's t-test. P-values indicate statistical significance between groups. N/A: Not Applicable. Data are not available for the control group as the exercise was not performed by this group.

Postoperative Complications

The incidence of postoperative complications is shown in Table 3. Overall postoperative complications, the primary endpoint, were observed in 48.1% and 44.4% of the control and intervention groups, respectively (relative risk (RR) 0.92, 95% confidence interval (CI) 0.57–2.07). Postoperative delirium occurred in 25.9% and 33.3% of the control and intervention groups, respectively (RR 1.29, 95% CI 0.31–1.94). No statistically significant differences were observed between the groups.

Table 3. Incidence of postoperative complications and one-year follow-up results in frail cancer patients

Variable	Control Group (n=27)	Intervention Group (n=18)	95% CI
Postoperative Complications (%)	13 (48.1%)	8 (44.4%)	0.57–2.07
Postoperative Delirium (%)	7 (25.9%)	6 (33.3%)	0.31–1.94
One-Year Follow-Up Results:
Death	4 (14.8%)	1 (5.6%)	0.01–3.92
Decreased ADL or Death	11 (42.3%)	4 (23.5%)	0.08–1.92

Postoperative complications and delirium are presented as counts and percentages. One-year follow-up results, including death and decreased activities of daily living (ADL), are also shown. In the intervention group, the evaluation of ADL was not available in one participant. The 95% confidence interval (95% CI) was provided for comparison between the groups.

Changes in Physical Function

The changes in physical function over time are shown in Figure 2. Grip strength was almost identical between the two groups at all three time points, with differences of less than 1% (preoperatively: 99.5±8.9% vs 100.1±19.2%, p=0.88; discharge: 96.0±9.0% vs 97.5±14.5%, p=0.70). Knee extension strength increased to 119.1% preoperatively in the intervention group; however, no significant difference was observed between the groups. Knee extension strength decreased to 86.7% in the control group but was maintained at 119.3% in the intervention group at discharge, with a significant difference between the groups (preoperatively: 100.2±18.3% vs 119.1±68.8%, p=0.19; discharge: 86.7±22.0% vs 119.3±72.0%, p=0.044). Walking speed and SMI showed similar trends, with a decrease in the control group at discharge; however, the difference between the groups was not significant (walking speed: preoperatively: 98.1±25.9% vs 115.7±60.5%, p=0.16; discharge: 80.0±22.4% vs 92.5±50.0%, p=0.29; SMI: preoperatively: 99.8±7.1% vs 101.3±5.1%, p=0.45; discharge: 91.9±8.8% vs 95.1±11.4%, p=0.34).

One-Year Follow-Up

The results of the one-year follow-up survey are presented in Table 3. Overall, 14.8% of participants in the control group and 5.6% in the intervention group died during the one-year follow-up period (RR 0.38, 95% CI 0.01–3.92). The proportion of patients with decreased ADL or death was lower in the intervention group than in the control group; however, the difference was not statistically significant (42.3% in the control group vs 23.5% in the intervention group; RR 0.56, 95% CI 0.08–1.92).

This study investigated the effect of preoperative exercise and nutritional intervention on the frequency of postoperative complications and physical function in frail older patients who underwent surgery for gastrointestinal cancer. While the intervention was feasible and safe, no significant differences were observed in the incidence of postoperative complications. However, the intervention group showed a trend towards better maintenance of physical function at discharge, suggesting that a two-week preoperative exercise and nutritional intervention may contribute to maintaining physical function during the perioperative period, even if it does not directly impact the incidence of postoperative complications.

Evidence supporting prehabilitation for maintaining postoperative physical function is increasing; however, no consensus exists on whether it reduces postoperative complications.[35, 36] Some studies have shown respiratory prehabilitation improves postoperative respiratory function[35, 37] and reduces the frequency of aspiration pneumonia.[38] A four-week prehabilitation for colorectal cancer contributes to maintaining postoperative physical function compared to postoperative rehabilitation, without a significant difference in the frequency of postoperative complications.[39] A randomized controlled trial of frail older patients with colorectal cancer showed that a CGA-based intervention did not improve the frequency of complications or 30-day postoperative outcomes.[40] Our study differs from previous studies in that we targeted older patients with decreased physical function, a component of frailty, including high-risk patients with gastrointestinal cancer, and the prescription of combined resistance exercise with amino acid supplementation to counteract the decline in physical function and malnutrition. The frequency of postoperative complications was lower in the intervention group; however, the difference was not statistically significant. In this study, the exercise intervention targeted the gluteal and lower limb muscles, which may not contribute to improving respiratory function, and potentially explain the lack of a significant reduction in the incidence of complications. Falls were not examined in this study, which could be a potential area for future research considering the direct relationship between the function of the lower limb muscles and fall prevention. Additionally, the interpretation of the trend toward increased postoperative delirium in the intervention group should be approached with caution. Exercise-induced fatigue and metabolic changes due to amino acid intake may contribute to delirium. Previous studies have reported a link between serum amino acid levels and the risk of delirium.[41]

Perioperative skeletal muscle function was better maintained in the intervention group than in the control group. Muscle strength and mass can increase after 8–12 weeks of exercise, even in older adults.[23, 24] Maintaining physical function is crucial in older adults as it affects levels of social activity and QOL, resulting in a decline in physical function observed after short-term intervention in this study.

Several considerations for improving the intervention methods exist. The selection criteria for the participants, as well as the duration and type of intervention, may have influenced the results of this study. Additionally, we targeted patients with decreased grip strength or walking speed. Our previous study showed knee extension strength had a stronger correlation with survival prognosis than grip strength.[13] The findings of the present work showed minimal changes in grip strength during the perioperative period. Grip strength may not be the best indicator of the effectiveness of training,[42] which is supported by this study. Therefore, selecting patients based on knee extension strength may identify those requiring intervention more accurately. Additionally, the intervention period is limited by the scheduled surgery, with most preoperative interventions lasting 2–4 weeks in systematic reviews.[36, 43, 44] Several types of interventions, including aerobic exercises, resistance exercises, balance exercises, and stretching, are considered effective for improving frailty.[45, 46] Vitamin D deficiency is associated with low muscle power and mass,[47] and supplementation has potential benefits in improving skeletal muscle function. Combining psychological and social support may further enhance the effectiveness of intervention.[17, 18]

In this study, preoperative exercise and nutritional interventions in frail older patients undergoing surgery for gastrointestinal cancer did not significantly reduce postoperative complications. However, it aided in maintaining physical function at discharge. The results suggest that preoperative interventions targeting physical function, a component of frailty, can help maintain QOL post-discharge. Future research should focus on optimizing perioperative interventions to ensure the safety and maintenance of ADL in older adults.

Limitations

We did not conduct intent-to-treat, survival, or multivariate analyses owing to the limited number of outcome events. The cut-off value of grip strength for males was set at < 26 kg according to the J-CHS criteria[48] at the time of study initiation, despite the 2019 Asian Working Group for Sarcopenia (AWGS)[49] and revised J-CHS criteria[33] suggesting < 28 kg.

The lack of difference in the average steps and total energy expenditure between the two groups during the two-week preoperative period may have been influenced by the Hawthorne effect[50] in the control group and the inability to detect resistance exercises using activity trackers. However, the independent contributions of exercise and nutritional therapy could not be assessed in this study. Furthermore, since this was a single-center study conducted at a university hospital and targeted older patients with decreased physical function, selection bias may have existed. Therefore, the findings may not be generalizable to cancer care in general community hospitals. Additional research is required to determine the validity of similar interventions in older patients without frailty.

This study investigated the effects of preoperative exercise and nutritional interventions in frail older patients undergoing gastrointestinal cancer surgery. The 14-day resistance exercise and amino acid supplementation did not significantly reduce the incidence of postoperative complications. Nevertheless, this intervention contributed to the maintenance of physical function at discharge.

These findings highlight the potential benefits of preoperative interventions in maintaining physical function and QOL in older adults undergoing surgery. In particular, knee extension strength was significantly maintained in the intervention group at discharge, indicating that such interventions could improve post-discharge QOL. Furthermore, the proportion of patients with decreased ADL or death was lower in the intervention group at one-year follow-up, suggesting positive long-term effects of the intervention. Further research is required to determine the optimal preoperative intervention methods. Nevertheless, the results of this study suggest that comprehensive measures for frailty, including exercise and nutrition, are effective even in the context of preoperative care for gastrointestinal cancer surgery.

Therefore, future studies should aim to optimize perioperative interventions to ensure safety and maintain ADL to improve long-term outcomes in older patients.

ADL: activities of daily living

AWGS: Asian Working Group for Sarcopenia

BMI: body mass index

CGA: comprehensive geriatric assessment

CI: confidence interval

GDS-15: Geriatric Depression Scale-15

IADL: Instrumental Activities of Daily Living

J-CHS: the Japanese version of the Cardiovascular Health Study criteria

MMSE: Mini-Mental State Examination

NYHA: New York Heart Association

PS: performance status

QOL: quality of life

REDCap: Research Electronic Data Capture

RR: relative risk

SMI: skeletal muscle mass index

Ethics approval and consent to participate

This study was approved by the Clinical Research Committee (Ethics Review Number 16124-4) and was registered with the University Hospital Medical Information Network (UMIN), Japan (UMIN000024526). This study was conducted in accordance with the Declaration of Helsinki of 1964 and its later amendments or comparable ethical standards.

Written informed consent was obtained from all participants, and all participants were assured of their right to withdraw consent.

Consent for publication

Not applicable

Availability of data and materials

Drs. T.F. and H.A. have full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Data generated in this study, consisting of deidentified participant data, will be made available upon request to the corresponding author starting from the date of publication. While there are no supporting documents available, researchers whose proposed use of the data has been approved can access it for specific purposes, such as conducting a meta-analysis. Access to the data will be provided through a signed data access agreement, with no additional restrictions.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by JSPS KAKENHI (grant number 16H05277).

Authors' contributions

Concept and design: HA, YY, KS, HR, KY; Acquisition, analysis, or interpretation of data: YY, MS, MT, MI, TF; Drafting of the manuscript: TF, HA, KS, KY; Critical review of the manuscript for important intellectual content: All authors; Statistical analysis: TF, HA, YY; Obtained funding: HR; Administrative, technical, or material support: MS, YY; Supervision: KS, HR, KY; Provision of therapy intervention for all patients and the educational program: MS, MT, MI, and YY.

Acknowledgments

We would like to thank Editage (www.editage.jp) for English language editing.

The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Etzioni DA, Liu JH, Maggard MA, Ko CY. The aging population and its impact on the surgery workforce. Ann Surg. 2003;238:170–7.
Vermeiren S, Vella-Azzopardi R, Beckwée D, Habbig A-K, Scafoglieri A, Jansen B, et al. Frailty and the Prediction of Negative Health Outcomes: A Meta-Analysis. J Am Med Dir Assoc. 2016;17:1163.e1-1163.e17.
Lin H-S, Watts JN, Peel NM, Hubbard RE. Frailty and post-operative outcomes in older surgical patients: a systematic review. BMC Geriatr. 2016;16:157.
Cacciatore F, Abete P, Mazzella F, Viati L, Della Morte D, D’Ambrosio D, et al. Frailty predicts long-term mortality in elderly subjects with chronic heart failure. Eur J Clin Invest. 2005;35:723–30.
Handforth C, Clegg A, Young C, Simpkins S, Seymour MT, Selby PJ, et al. The prevalence and outcomes of frailty in older cancer patients: a systematic review. Ann Oncol. 2015;26:1091–101.
Ravasco P, Monteiro-Grillo I, Vidal PM, Camilo ME. Cancer: disease and nutrition are key determinants of patients’ quality of life. Support Care Cancer. 2004;12:246–52.
Arends J, Baracos V, Bertz H, Bozzetti F, Calder PC, Deutz NEP, et al. ESPEN expert group recommendations for action against cancer-related malnutrition. Clin Nutr. 2017;36:1187–96.
Mazaki T, Ebisawa K. Enteral versus parenteral nutrition after gastrointestinal surgery: a systematic review and meta-analysis of randomized controlled trials in the English literature. J Gastrointest Surg. 2008;12:739–55.
Salzman GA, Saliba D, Ko CY, Maggard-Gibbons M, Russell MM. The Association of Frailty With Outcomes for Older Adults Undergoing Appendectomy. Am Surg. 2022;88:2456–63.
Vermillion SA, Hsu F-C, Dorrell RD, Shen P, Clark CJ. Modified frailty index predicts postoperative outcomes in older gastrointestinal cancer patients. J Surg Oncol. 2017;115:997–1003.
Giannotti C, Sambuceti S, Signori A, Ballestrero A, Murialdo R, Romairone E, et al. Frailty assessment in elective gastrointestinal oncogeriatric surgery: Predictors of one-year mortality and functional status. J Geriatr Oncol. 2019;10:716–23.
Maekawa Y, Sugimoto K, Yamasaki M, Takeya Y, Yamamoto K, Ohishi M, et al. Comprehensive Geriatric Assessment is a useful predictive tool for postoperative delirium after gastrointestinal surgery in old-old adults. Geriatr Gerontol Int. 2016;16:1036–42.
Yasunobe Y, Akasaka H, Yamamoto K, Sugimoto K, Maekawa Y, Onishi Y, et al. Knee Extensor Weakness Potently Predicts Postoperative Outcomes in Older Gastrointestinal Cancer Patients. J Am Med Dir Assoc. 2024;25:98–103.
Yamasaki M, Maekawa Y, Sugimoto K, Mizushima T, Eguchi H, Ogihara T, et al. Development of a Geriatric Prognostic Scoring System for Predicting Survival After Surgery for Elderly Patients With Gastrointestinal Cancer. Ann Surg Oncol. 2019;26:3644–51.
Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146-56.
Clegg A, Young J. The frailty syndrome. Clin Med . 2011;11:72–5.
Luger E, Dorner TE, Haider S, Kapan A, Lackinger C, Schindler K. Effects of a Home-Based and Volunteer-Administered Physical Training, Nutritional, and Social Support Program on Malnutrition and Frailty in Older Persons: A Randomized Controlled Trial. J Am Med Dir Assoc. 2016;17:671.e9-671.e16.
Ng TP, Feng L, Nyunt MSZ, Feng L, Niti M, Tan BY, et al. Nutritional, Physical, Cognitive, and Combination Interventions and Frailty Reversal Among Older Adults: A Randomized Controlled Trial. Am J Med. 2015;128:1225-1236.e1.
Soysal P, Stubbs B, Lucato P, Luchini C, Solmi M, Peluso R, et al. Inflammation and frailty in the elderly: A systematic review and meta-analysis. Ageing Res Rev. 2016;31:1–8.
Campins L, Camps M, Riera A, Pleguezuelos E, Yebenes JC, Serra-Prat M. Oral Drugs Related with Muscle Wasting and Sarcopenia. A Review. Pharmacology. 2017;99:1–8.
Simonsen C, de Heer P, Bjerre ED, Suetta C, Hojman P, Pedersen BK, et al. Sarcopenia and Postoperative Complication Risk in Gastrointestinal Surgical Oncology: A Meta-analysis. Ann Surg. 2018;268:58–69.
Nakamura R, Inage Y, Tobita R, Yoneyama S, Numata T, Ota K, et al. Sarcopenia in Resected NSCLC: Effect on Postoperative Outcomes. J Thorac Oncol. 2018;13:895–903.
Harridge SD, Kryger A, Stensgaard A. Knee extensor strength, activation, and size in very elderly people following strength training. Muscle Nerve. 1999;22:831–9.
Lee H, Kim I-G, Sung C, Jeon T-B, Cho K, Ha Y-C, et al. Exercise training increases skeletal muscle strength independent of hypertrophy in older adults aged 75 years and older. Geriatr Gerontol Int. 2019;19:265–70.
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403.
Lynch CJ, Halle B, Fujii H, Vary TC, Wallin R, Damuni Z, et al. Potential role of leucine metabolism in the leucine-signaling pathway involving mTOR. Am J Physiol Endocrinol Metab. 2003;285:E854-63.
Dodd KM, Tee AR. Leucine and mTORC1: a complex relationship. Am J Physiol Endocrinol Metab. 2012;302:E1329-42.
Hannaian SJ, Hodson N, Abou Sawan S, Mazzulla M, Kato H, Matsunaga K, et al. Leucine-enriched amino acids maintain peripheral mTOR-Rheb localization independent of myofibrillar protein synthesis and mTORC1 signaling postexercise. J Appl Physiol. 2020;129:133–43.
Smith GI, Yoshino J, Stromsdorfer KL, Klein SJ, Magkos F, Reeds DN, et al. Protein Ingestion Induces Muscle Insulin Resistance Independent of Leucine-Mediated mTOR Activation. Diabetes. 2015;64:1555–63.
Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. Int J Surg. 2012;10:28–55.
Sugishita M. The validity and reliability of the Japanese version of the Mini-Mental State Examination (MMSE-J). Ninchi Shinkei Kagaku. 2018;20:91.
Starkstein SE, Fedoroff JP, Price TR, Leiguarda R, Robinson RG. Apathy following cerebrovascular lesions. Stroke. 1993;24:1625–30.
Satake S, Arai H. The revised Japanese version of the Cardiovascular Health Study criteria (revised J-CHS criteria). Geriatr Gerontol Int. 2020;20:992–3.
Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’for medical statistics. Bone Marrow Transplant. 2013;48:452–8.
Sanchez-Lorente D, Navarro-Ripoll R, Guzman R, Moises J, Gimeno E, Boada M, et al. Prehabilitation in thoracic surgery. J Thorac Dis. 2018;10 Suppl 22:S2593–600.
Hijazi Y, Gondal U, Aziz O. A systematic review of prehabilitation programs in abdominal cancer surgery. Int J Surg. 2017;39:156–62.
Dezube AR, Cooper L, Jaklitsch MT. Prehabilitation of the Thoracic Surgery Patient. Thorac Surg Clin. 2020;30:249–58.
Yamana I, Takeno S, Hashimoto T, Maki K, Shibata R, Shiwaku H, et al. Randomized Controlled Study to Evaluate the Efficacy of a Preoperative Respiratory Rehabilitation Program to Prevent Postoperative Pulmonary Complications after Esophagectomy. Dig Surg. 2015;32:331–7.
Gillis C, Li C, Lee L, Awasthi R, Augustin B, Gamsa A, et al. Prehabilitation versus rehabilitation: a randomized control trial in patients undergoing colorectal resection for cancer. Anesthesiology. 2014;121:937–47.
Ommundsen N, Wyller TB, Nesbakken A, Bakka AO, Jordhøy MS, Skovlund E, et al. Preoperative geriatric assessment and tailored interventions in frail older patients with colorectal cancer: a randomized controlled trial. Colorectal Dis. 2018;20:16–25.
Pandharipande PP, Morandi A, Adams JR, Girard TD, Thompson JL, Shintani AK, et al. Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients. Intensive Care Med. 2009;35:1886–92.
Tieland M, Verdijk LB, de Groot LCPGM, van Loon LJC. Handgrip strength does not represent an appropriate measure to evaluate changes in muscle strength during an exercise intervention program in frail older people. Int J Sport Nutr Exerc Metab. 2015;25:27–36.
Chang MC, Choo YJ, Kim S. Effect of prehabilitation on patients with frailty undergoing colorectal cancer surgery: a systematic review and meta-analysis. Ann Surg Treat Res. 2023;104:313–24.
Kamarajah SK, Bundred J, Weblin J, Tan BHL. Critical appraisal on the impact of preoperative rehabilitation and outcomes after major abdominal and cardiothoracic surgery: A systematic review and meta-analysis. Surgery. 2020;167:540–9.
Pinheiro MB, Oliveira JS, Baldwin JN, Hassett L, Costa N, Gilchrist H, et al. Impact of physical activity programs and services for older adults: a rapid review. Int J Behav Nutr Phys Act. 2022;19:87.
Apóstolo J, Cooke R, Bobrowicz-Campos E, Santana S, Marcucci M, Cano A, et al. Effectiveness of interventions to prevent pre-frailty and frailty progression in older adults: a systematic review. JBI Database System Rev Implement Rep. 2018;16:140–232.
Onishi Y, Akasaka H, Hatta K, Terashima K, Yoshida S, Yasunobe Y, et al. Association between serum vitamin D levels and skeletal muscle indices in an older Japanese population: The SONIC study. Geriatr Gerontol Int. 2024. https://doi.org/10.1111/ggi.14951.
Satake S, Shimada H, Yamada M, Kim H, Yoshida H, Gondo Y, et al. Prevalence of frailty among community-dwellers and outpatients in Japan as defined by the Japanese version of the Cardiovascular Health Study criteria. Geriatr Gerontol Int. 2017;17:2629–34.
Chen L-K, Woo J, Assantachai P, Auyeung T-W, Chou M-Y, Iijima K, et al. Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment. J Am Med Dir Assoc. 2020;21:300-307.e2.
Adair JG. The Hawthorne effect: A reconsideration of the methodological artifact. J Appl Psychol. 1984;69:334–45.

No competing interests reported.

Pre-Operative Resistance Training and Amino Acid Supplementation in Frail Patients with Gastrointestinal Cancer: A Randomized Clinical Trial

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Trial Registration:

Figures

BACKGROUND

METHODS

RESULTS

DISCUSSION

Limitations

CONCLUSIONS

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1