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Pre-Operative Resistance Training and Amino Acid
Supplementation in Frail Patients with
Gastrointestinal Cancer: A Randomized Clinical Trial
Taku Fujimoto
Osaka University Graduate School of Medicine
Hiroshi Akasaka
Osaka University Graduate School of Medicine
Yukiko Yasunobe
Osaka University Graduate School of Medicine
Shino Yoshida
Osaka University Graduate School of Medicine
Yuri Onishi
Osaka University Graduate School of Medicine
Tomohiro Minami
Osaka University Graduate School of Medicine
Ken Terashima
Osaka University Graduate School of Medicine
Mari Shirai
Osaka University Graduate School of Medicine
Masaaki Isaka
Osaka University Graduate School of Medicine
Minoru Tanaka
Osaka University Graduate School of Medicine
Ken Sugimoto
Kawasaki Medical School
Hiroshi Koriyama
Osaka University Graduate School of Medicine
Yoichi Takami
Osaka University Graduate School of Medicine
Makoto Yamasaki
Kansai Medical University
Kotaro Yamashita
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Osaka University Graduate School of Medicine
Takehiro Noda
Osaka University Graduate School of Medicine
Hidekazu Takahashi
Osaka University Graduate School of Medicine
Hidetoshi Eguchi
Osaka University Graduate School of Medicine
Yuichiro Doki
Osaka University Graduate School of Medicine
Hiromi Rakugi
Osaka University Graduate School of Medicine
Koichi Yamamoto
Osaka University Graduate School of Medicine
Research Article
Keywords: Preoperative frailty, preoperative exercise, amino acids, gastrointestinal cancer
Posted Date: October 30th, 2024
DOI: https://doi.org/10.21203/rs.3.rs-5257948/v1
License: This work is licensed under a Creative Commons Attribution 4.0 International License.
Read Full License
Additional Declarations: No competing interests reported.
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Abstract
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
signicance 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% condence 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 signicant 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 signicantly 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:
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UMIN (University Hospital Medical Information Network) Clinical Trials Registry (ID: UMIN000024526),
registered on 1 December 2016.
BACKGROUND
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 inuenced 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 signicantly 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, inammation, 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
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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.
METHODS
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 dened as grip strength < 26 kg in men and < 18 kg
in women, whereas decreased walking speed was dened as walking speed < 1.0 m/s. The exclusion
criteria were patients with exertional angina, chronic heart failure (New York Heart Association [NYHA]
classication II or higher), tachyarrhythmia, chronic respiratory failure (Hugh-Jones classication II or
higher), active multiple cancers, chronic renal failure (estimated glomerular ltration 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 stratied by age, MMSE score,
and Geriatric Depression Scale-15 (GDS-15) using REDCap, which provided an independent and
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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 conrmed 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 ve 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
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Statistical Computing, Vienna, Austria). This is a modied 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 dicult, 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 signicance was set at p <0.05.
RESULTS
Participants
The owchart 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: ve withdrew consent, six had
changes in treatment plans, ve 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 signicant 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 signicant 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 signicant differences. The serological evaluation revealed no signicant differences in
hemoglobin, serum albumin, serum creatinine, and serum C-reactive protein values between the two
groups.
Table 1.Baseline characteristics
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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
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- 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
signicance 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
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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 signicance 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% condence 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 signicant 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% condence interval (95% CI)
was provided for comparison between the groups.
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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 signicant 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 signicant 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 signicant (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 signicant (42.3% in the
control group vs 23.5% in the intervention group; RR 0.56, 95% CI 0.08–1.92).
DISCUSSION
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 signicant 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
signicant 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
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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 signicant. 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 signicant 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 inuenced 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 ndings 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 deciency is associated
with low muscle power and mass,[47] and supplementation has potential benets 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 signicantly 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
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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 inuenced 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 ndings 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.
CONCLUSIONS
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 signicantly reduce the incidence of postoperative complications. Nevertheless,
this intervention contributed to the maintenance of physical function at discharge.
These ndings highlight the potential benets of preoperative interventions in maintaining physical
function and QOL in older adults undergoing surgery. In particular, knee extension strength was
signicantly 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.
Abbreviations
ADL: activities of daily living
AWGS: Asian Working Group for Sarcopenia
BMI: body mass index
CGA: comprehensive geriatric assessment
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CI: condence 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
Declarations
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 deidentied 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
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specic 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.
References
1. Etzioni DA, Liu JH, Maggard MA, Ko CY. The aging population and its impact on the surgery
workforce. Ann Surg. 2003;238:170–7.
2. 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.
3. 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.
4. 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.
5. 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.
Page 16/20
7. 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.
9. 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.
10. Vermillion SA, Hsu F-C, Dorrell RD, Shen P, Clark CJ. Modied frailty index predicts postoperative
outcomes in older gastrointestinal cancer patients. J Surg Oncol. 2017;115:997–1003.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
1. Clegg A, Young J. The frailty syndrome. Clin Med . 2011;11:72–5.
17. 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.
1. 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.
19. Soysal P, Stubbs B, Lucato P, Luchini C, Solmi M, Peluso R, et al. Inammation and frailty in the
elderly: A systematic review and meta-analysis. Ageing Res Rev. 2016;31:1–8.
20. 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.
21. 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.
Page 17/20
22. 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.
23. 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.
24. 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.
25. 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.
2. 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.
27. Dodd KM, Tee AR. Leucine and mTORC1: a complex relationship. Am J Physiol Endocrinol Metab.
2012;302:E1329-42.
2. 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 myobrillar protein
synthesis and mTORC1 signaling postexercise. J Appl Physiol. 2020;129:133–43.
29. 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.
30. 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.
31. Sugishita M. The validity and reliability of the Japanese version of the Mini-Mental State
Examination (MMSE-J). Ninchi Shinkei Kagaku. 2018;20:91.
32. Starkstein SE, Fedoroff JP, Price TR, Leiguarda R, Robinson RG. Apathy following cerebrovascular
lesions. Stroke. 1993;24:1625–30.
33. 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.
34. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’for medical statistics. Bone
Marrow Transplant. 2013;48:452–8.
35. 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.
3. Hijazi Y, Gondal U, Aziz O. A systematic review of prehabilitation programs in abdominal cancer
surgery. Int J Surg. 2017;39:156–62.
37. Dezube AR, Cooper L, Jaklitsch MT. Prehabilitation of the Thoracic Surgery Patient. Thorac Surg Clin.
2020;30:249–58.
Page 18/20
3. Yamana I, Takeno S, Hashimoto T, Maki K, Shibata R, Shiwaku H, et al. Randomized Controlled Study
to Evaluate the Ecacy of a Preoperative Respiratory Rehabilitation Program to Prevent
Postoperative Pulmonary Complications after Esophagectomy. Dig Surg. 2015;32:331–7.
39. 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.
40. 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.
41. 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.
42. 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.
43. 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.
44. 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.
45. 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.
4. 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.
47. 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.
4. 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 dened by the Japanese version of the
Cardiovascular Health Study criteria. Geriatr Gerontol Int. 2017;17:2629–34.
49. 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.
50. Adair JG. The Hawthorne effect: A reconsideration of the methodological artifact. J Appl Psychol.
1984;69:334–45.
Figures
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Figure 1
Flowchart of the study and participants
The owchart shows recruitment, randomization, and analysis of study participants. Of the 62 patients
who provided consent, 17 were excluded. The nal analysis included 45 patients, with 27 and 18 in the
control and intervention groups, respectively. All participants were followed up for one year for survival;
however, the evaluation data were missing for one participant in each group.
Page 20/20
Figure 2
Changes in physical function over time
The graphs show the percentage changes from baseline in grip strength, knee extension strength,
walking speed, and skeletal muscle index (SMI) at three time points: two weeks preoperatively,
immediately preoperatively, and at discharge. Values are presented as mean ± SD. Statistical signicance
between groups was assessed using the Student's t-test. *p<0.05, indicates a signicant difference in
knee extension strength between the groups at discharge.
