Effect of Branched-Chain Amino Acid-enriched nutritional supplement after exercise on skeletal muscle mass in patients undergoing surgery for gastrointestinal cancer

ABSTRACT

Objectives:

To investigate the effects of branched-chain amino acid (BCAA)-enriched nutritional supplementation after exercise on skeletal muscle and walking ability in patients undergoing gastrointestinal cancer surgery.

Methods:

Fifty patients with gastric or colorectal cancer scheduled for surgery were enrolled in this single-center, single-blind, randomized controlled study. Patients were randomly assigned to a BCAA-enriched jelly group (test group) or an amino acid-free jelly group (control group). Both groups received perioperative exercise therapy and jelly supplementation immediately after exercise. The primary endpoints were percentage changes in thigh skeletal muscle area from pre-intervention to 9 weeks after discharge and from 2 weeks after surgery to 9 weeks after discharge. Secondary endpoints were changes in isometric knee extension and flexion strength and 6-minute walk distance.

Results:

One patient withdrew consent; therefore, the full analysis set consisted of 24 patients in the test group and 25 patients in the control group. The percentage changes in quadriceps area from pre-intervention to 9 weeks after discharge were 3.24 ± 6.63% and 2.34 ± 16.59% in the test and control groups, respectively, with no significant difference. From 2 weeks after surgery to 9 weeks after discharge, the changes were 8.40 ± 7.57% and 4.44 ± 12.93%, respectively, with no significant difference. No significant differences were observed in hamstring area, lower-limb strength, or 6-minute walk distance between the two groups.

Conclusions:

Perioperative exercise therapy combined with BCAA-enriched supplementation did not significantly improve thigh skeletal muscle area, muscle strength, or walking ability after surgery in patients undergoing gastrointestinal cancer surgery compared with amino acid-free supplementation. Further studies with adequate sample sizes and higher BCAA intake are warranted.

INTRODUCTION

The number of cancer surgeries is increasing annually worldwide, with more than 9 million surgeries performed in 2018. This number is expected to reach more than 14 million in 2040.¹⁾ Surgery is essential for the treatment of solid cancers; however, it is well known that surgery has a negative impact on the patient’s quality of life and function.²⁾ Even if patients survive surgery, post-cancer surgery problems, mainly functional impairment,^3,4) are considered to be a barrier to returning to work and are significantly associated with early retirement.^5,6)

Prehabilitation is attracting attention as a perioperative intervention aimed at minimizing the functional impairment that occurs after surgery.^7,8) Prehabilitation focuses on exercise (aerobic training, strength training), nutritional support, and psychosocial support.⁹⁾ Among the postoperative physical disabilities of cancer patients, muscle weakness and loss of muscle mass are particularly limiting for activities of daily living (ADL). The most important factor for cancer patients to return to work is to maintain and improve their physical strength, and exercise therapy is the most effective way to achieve this.⁹⁾ In addition to improving skeletal muscle mass and maximal oxygen uptake (VO₂max), exercise therapy has recently been shown to have a positive effect on mental function.¹⁰⁾

We have reported that preoperative rehabilitation therapy in patients undergoing surgery for gastrointestinal cancer improves cardiopulmonary function and muscle strength and that this has a positive effect on the postoperative course.¹¹⁾ Patients undergoing pancreatoduodenectomy who received preoperative and postoperative rehabilitation treatment had a significantly lower rate of postoperative respiratory complications and a significantly shorter hospital stay than patients who did not receive perioperative rehabilitation treatment. These results indicate that preoperative and postoperative rehabilitation treatments can increase preoperative fitness and significantly reduce postoperative complications.¹²⁾

Nutritional supplementation containing protein has been reported to enhance skeletal muscle mass during exercise.¹³⁾ It has also been reported that the best time to take supplements is immediately after exercise, because no significant enhancing effect is observed after 2 h.¹⁴⁾ Okazaki et al.¹⁵⁾ conducted an intervention study to investigate the combined effects of exercise and protein supplementation in a randomized trial of healthy young and middle-aged subjects. They reported that in middle-aged and elderly women, the group that took protein supplements within 30 min immediately after interval walking exercise had significantly increased lower-limb muscle cross-sectional area and maximum flexion muscle strength in comparison to the group that did not take protein supplements.¹⁵⁾ Protein intake also produces a strong anabolic stimulus that increases muscle protein synthesis, the ability of which depends on the amino acid composition ingested, with the main effects being attributed to essential amino acids.¹⁶⁾ Ingestion of essential amino acids, branched chain amino acids (BCAA), and supplements high in leucine has been shown to increase muscle mass, strength, and walking ability.^17,18,19) A randomized controlled trial (RCT) demonstrated the muscle-enhancing effect of BCAA-rich nutritional supplements after exercise therapy. It has been reported that patients with walking disorders who took a BCAA-rich nutritional supplement within 30 min of exercise showed a significant increase in muscle mass in comparison to a group that did not take anything.²⁰⁾ It has also been reported that in post-stroke patients, BCAA-rich dietary supplements taken within 30 min of exercise significantly increased muscle mass and strength.²¹⁾

These findings suggest that combining exercise therapy with BCAA-rich amino acid intake after surgery may be beneficial for the recovery of the postoperative physical function in patients with gastrointestinal cancer. Recently, it has been reported that BCAA-rich supplementation and exercise therapy during the first postoperative month restored skeletal muscle mass and quality of life in postoperative patients with gastric cancer, which declined during the first postoperative week.²²⁾ However, the study was not comparative, and its effects did not clarify the usefulness of taking BCAA-rich supplements. To date, no study has demonstrated the benefits of BCAA-rich supplementation in conjunction with exercise therapy for patients undergoing surgery for gastrointestinal cancer.

This study aimed to investigate the effects of exercise therapy followed immediately by carbohydrate plus BCAA-rich nutrition on skeletal muscle mass, strength, and walking ability in relation to post-operative ADL improvement in comparison to exercise therapy plus carbohydrate alone in patients undergoing gastrointestinal cancer surgery.

MATERIALS AND METHODS

Study Design

This was a single-center, parallel-group, randomized, single-blind, placebo-controlled superiority study. This study was registered in the UMIN Clinical Trials Registry (UMIN000036022) and was conducted according to a protocol reviewed and approved by the Ethics Committee of Wakayama Rosai Hospital (18–21). All patients provided their written informed consent before participation. This study was performed in accordance with the principles of the Declaration of Helsinki.

Patients

The subjects were patients with gastric or colorectal cancer scheduled to undergo surgery between May 2019 and June 2022 at Wakayama Rosai Hospital. The following eligibility criteria were used: aged 20–90 years at the time of consent; ability to be hospitalized for 10 days before surgery to approximately 2 weeks after surgery; and ability to visit the hospital once or twice a week for 9 weeks after discharge. Patients were excluded according to the following criteria: poorly controlled diabetes mellitus, unstable angina pectoris, serious liver disease, serious renal disease; difficulty continuing exercise because of osteoarticular disease or cerebrovascular disease; anticancer drug intake within 1 month; pregnancy or likely to become pregnant; breastfeeding; COVID-19 infection; and patients who were judged to be unsuitable as subjects by the principal investigator or a research assistant. The suitability of each patient for exercise therapy was confirmed by a research physician, and the required patient information was submitted to the Data Center (Department of Medical Innovation, Osaka University School of Medicine) using the electronic data capture system (DATATRAK ONE).

Allocation Method and Allocation Adjustment Factors

An assignment coordinator performed dynamic random allocation within the DATATRAK ONE system. Enrolled patients were randomly assigned to either the test treatment group (test group) or the control treatment group (control group). The following allocation adjustment factors were used: age (≥70 years /<70 years), sex (male/female), diagnosis, and planned operation (gastric cancer, total gastrectomy, gastric cancer, distal gastrectomy, or colorectal cancer). Allocation information was stored within the system and remained inaccessible except for the following circumstances: the jelly labeling personnel needed to verify group information; the assignment coordinator at the Data Center needed to check information in emergencies; unlocking the system at the end of the study. After the study concluded, a data manager who was not involved in the allocation process verified and extracted the data for analysis.

Rehabilitation Programs and Nutritional Support

The treatment protocol consisted of exercise therapy (strengthening of cardiopulmonary function and muscle strength training) and nutritional support therapy (intake of jelly).

Exercise Therapy

Prior to admission, maximal oxygen uptake (VO2peak) was measured using an expiratory gas analyzer (AERO AE310; Minato Medical Science, Osaka, Japan) during a progressive exercise load test on a bicycle ergometer before the first exercise therapy session. From hospital admission through the 10 days before surgery and for 2 weeks after surgery (up to the day before discharge): the patient performed 30 min of cardiopulmonary function training using a cycle ergometer and treadmill walking (exercise load was 60% of maximum oxygen intake), muscle-strengthening squats (six sets of 50 repetitions), and training with knee exercise equipment (COMBIT CB-2; Minato Medical Science) (three sets of ten repetitions at 70% of maximal muscle strength load). These exercises were performed once a day under the supervision of a physiotherapist. These exercises were carried out 7 days out of approximately 10 days before surgery, as well as 5 days per week in the 2 weeks after surgery, starting from the day after the operation.

Until 9 weeks after discharge, the patient performed the exercises as described above on the outpatient visit day (1 or 2 days/week). On days other than the outpatient visit day, patients performed walking at a pulse rate equivalent to 60% of VO2peak and muscle-strengthening squats (six sets of 50 repetitions) once a day, as instructed by a physiotherapist. To monitor adherence to exercise therapy at home, we asked patients to record the time, number of repetitions, and number of sets for each exercise item and submit this information. The rehabilitation achievement rate was defined as the percentage of total days on which patients completed at least 70% of the prescribed daily exercise therapy (endurance training and strength training).

Nutritional Support

Starting at approximately 10 days before surgery, patients consumed one pack of jelly food (corresponding to the patient’s allocation group) immediately after completing the exercise therapy session. No jelly foods were provided for the first week after surgery. From the seventh day after surgery until the day before discharge, the subjects consumed one pack of jelly food immediately after completing the exercise therapy session. Until 9 weeks after discharge, patients consumed one pack of jelly food on the outpatient visit day (1 or 2 days/week) immediately after completing the exercises.

The physical therapist provided five or six packs of jelly supplement (corresponding to the assigned group) to the subject (for the number of days in a week, excluding hospital visits). On the day of the next outpatient visit, subjects brought all the jelly supplement packs they had consumed in the previous week and handed them over to the physical therapist at the hospital. On days other than the outpatient visit day, subjects consumed one pack of jelly supplement immediately after performing exercises at home. Subjects also consumed meals other than jelly as usual. The jelly intake achievement rate was defined as the percentage of total days on which patients consumed at least 70% of the prescribed daily jelly intake.

Nutritional Guidance and Diet Record

For nutritional guidance, the required protein intake excluding the jelly supplement was determined by considering the stress coefficient of surgery. The intake was set at 1.2 g/kg for colorectal cancer patients and 1.4 g/kg for gastric cancer patients for the first 2 weeks after surgery, 1.0 g/kg for colon cancer patients and 1.2 g/kg for gastric cancer patients from discharge until 4 weeks after discharge, and thereafter 1.0 g/kg for both colon cancer and gastric cancer patients.

At the start of the postoperative dietary therapy, the patient was provided with dietary guidance by a registered dietitian and instructions on how to complete their dietary records for the 2 weeks after surgery. Before discharge, we asked patients to record their actual daily meals for 1 day each week over the 4 weeks following discharge.

At the outpatient visit 4 weeks after discharge, the registered dietitian collected the patient’s dietary records and provided dietary guidance. Patients were also asked to record their diet for 1 day of each week from 4 weeks until 9 weeks after discharge. At the outpatient visit 9 weeks after discharge, the registered dietitian collected the patient’s dietary records and provided dietary guidance. Energy intake or protein intake of regular diets were calculated based on the dietary records submitted by the patients.

Intervention

The test group received protein-rich jelly (Reha-time Jelly; Clinico, Tokyo, Japan) and the control group received protein-free jelly (Qoo Jelly; Coca-Cola Japan, Tokyo, Japan). Reha-time Jelly contains 10 g of protein (2400 mg of branched amino acids, including 1400 mg of leucine) and 15 g of carbohydrate, with a total calorie content of 100 kcal. In contrast, Qoo Jelly contains no protein, but 22.5 g of carbohydrates, for a total calorie content of 90 kcal. In addition, to ensure that the Reha-time Jelly and Qoo Jelly were visually indistinguishable (subject blinding), a staff member masked the jelly packs. One type of jelly was given an “A” label, and the other was given a “B” label. It is assumed that no one other than the person in charge of labeling knew which jelly was labeled “A” or “B”. The physical therapists who handed the jelly to the patients were also blinded.

Outcome Measure

Medical staff that were blinded to the group allocations evaluated the outcomes. The primary endpoints were the percentage change in thigh skeletal muscle area from before exercise therapy with nutritional support to 9 weeks after discharge and the percentage change in thigh skeletal muscle area from 2 weeks after surgery to 9 weeks after discharge. The following secondary endpoints were used: changes in thigh skeletal muscle area (actual measurements), changes in functional independence measure (FIM) score (total score), changes in isometric knee extension and isometric knee flexion, changes in the 6-min walk distance (6MWD), number of adverse events, and frequency of adverse events.

The thigh skeletal muscle area was measured using computed tomography images of the cross-sectional area of the quadriceps and hamstrings at the midpoint of the line connecting the superior end of the femoral head and the inferior end of the medial malleolus. These measurements were performed by a single designated radiologist using the image analysis workstation (AZE VirtualPlace; AZE, Kawasaki, Japan). Measurements were taken three times, and the median value was adopted. The muscle strength of isometric knee extension and flexion was measured using the COMBIT CB-2 apparatus. Subjects were positioned in a mobile dynamometer chair with the hip joint fixed at 90°of flexion and the knee joint at 60° of flexion (0° = full extension). Following a standardized warm-up (light cycling exercise and two practice contractions at approximately 50% of maximum effort in each muscle group), three maximum voluntary contractions were performed in the knee extensor muscle group, followed by three maximum voluntary contractions in the knee flexor muscle group. Rest periods between each trial and between muscle groups were 60–90 s. The 6MWD was recorded as the longest distance that could be walked in 6 min on a 20-m straight course in the rehabilitation room.

Sample Size

The sample size to predict the number of patients necessary for statistical validity was based on a previous randomized study involving 35 healthy women.¹⁵⁾ When conducting a t-test with a significance level of 0.05, a power of 0.80, and a two-tailed alternative hypothesis, the number of cases required was 42 (21 in each group). To allow for a dropout rate of 10%, the study required 48 cases (24 in each group).

Statistical Analysis

Continuous variables were summarized as mean ± standard deviation (SD), and categorical variables were summarized as number (percentage). The primary analysis was conducted on the full analysis set (FAS), which was the total enrolled population excluding those who withdrew consent based on the intention-to-treat principle. In addition, the analyses were conducted on the per protocol set (PPS), excluding cases from the FAS in which the primary endpoint was unavailable, in which either the rehabilitation achievement rate or jelly intake rate was below 70%, and cases in which prohibited concomitant medications were used.

Baseline characteristics were compared between the two groups using Welch’s t-test, the chi-square test, and Wilcoxon signed-rank test. For efficacy analyses, Welch’s t-test was used for between-group comparisons at one time point, and a repeated measures analysis of variance was used for between-group comparisons over the observation time. A paired t-test was used for within-group comparisons at two time points. As post hoc analyses, a mixed-effects model for repeated measures (MMRM) was applied to the longitudinal data, adjusting for age and primary cancer. The safety analysis was summarized based on adverse events. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

RESULTS

A total of 50 patients were enrolled, and 1 patient assigned to the test group withdrew consent before intervention, thus resulting in a FAS that consisted of 24 patients in the test group and 25 patients in the control group. It took 3 years to accumulate 50 patients because of the COVID-19 pandemic that began in early 2020. In the test group, rehabilitation achievement or jelly intake rate was less than 70% in 2 patients, and 4 patients could not continue the intervention. In the control group, rehabilitation achievement or jelly intake rate was less than 70% in 3 patients, 1 patient could not continue the intervention, incomplete data were collected from 1 patient, and 1 patient received prohibited concomitant medications. Therefore, the PPS consisted of 18 patients in the test group and 19 patients in the control group (Fig. 1). The average age of patients in the test group was significantly older than that of the control group (P = 0.034). No difference was observed in other background factors. Factors related to the assessment items did not differ between the two groups (Table 1). There was no difference between the two groups in the achievement rate of neither rehabilitation nor jelly intake (Table 2). In addition, no significant difference was observed in energy intake or protein intake of regular diets between the two groups (Table 3).

Fig. 1.

 Flowchart of patient inclusion and follow-up.

Table 1.  Demographic and clinical characteristics of study participants.

Characteristic	Test group (n = 24)	Control group (n = 25)	P value
Age, years	77.0 ± 6.7	72.7 ± 7.1	0.034 a
Sex			0.889 b
Male	12	13
Female	12	12
Body weight, kg	57.0 ± 14.8	54.3 ± 10.9	0.468 a
Primary cancer			1.000 b
Stomach	3	4
Colorectal	21	21
Presence of comorbidity	17	15	0.426 b
Albumin, g/dL	3.84 ± 0.44	3.78 ± 0.39	0.633 a
Total protein, g/dL	6.88 ± 0.66	6.77 ± 0.50	0.511 a
Quadriceps muscle area, cm2	46.0 ± 12.8	45.0 ± 8.6	0.754 a
Hamstring area, cm2	19.0 ± 6.1	17.6 ± 3.1	0.355 a
FIM score	124.9 ± 2.8	125.4 ± 2.0	0.374 a
Isometric knee extension, Nm	98.0 ± 42.7	90.3 ± 40.6	0.531 a
Isometric knee flexion, Nm	33.0 ± 19.4	32.9 ± 17.0	0.982 a
6MWD, m	419.0 ± 83.1	428.3 ± 95.6	0.718 a

Data are presented as mean ± SD or as number.

^a Welch's t-test; ^b Chi-square test.

Table 2.  Achievement rate of exercise therapy and jelly intake.

Training	Test group (n = 24)	Control group (n = 25)	P value a
Cardiopulmonary strengthening	81.0 ± 22.1	84.1 ± 11.4	0.544
Muscle strengthening	83.0 ± 20.0	86.4 ± 9.3	0.447
Jelly intake	85.7± 22.4	88.9 ± 17.0	0.580

Achievement rate (%) data are presented as mean ± SD.

^a Welch's t-test.

Table 3.  Energy intake or protein intake of regular diets.

Daily dietary intake	One week after surgery		Two weeks after surgery		Four weeks after discharge		Nine weeks after discharge
	Test group	Control group	Test group	Control group	Test group	Control group	Test group	Control group
Patients analyzed	n = 21	n = 24	n = 22	n = 25	n = 20	n = 25	n = 20	n = 24
Energy intake, kcal/kg	18.35 ± 6.15	18.94 ± 5.24	26.01 ± 9.80	29.28 ± 6.54	31.98 ± 8.43	32.26 ± 7.33	32.91 ± 6.50	32.86 ± 7.41
P value	0.735		0.194		0.909		0.983
Protein intake, g/kg	0.79 ± 0.29	0.81 ± 0.28	1.08 ± 0.40	1.18 ± 0.28	1.41 ± 0.47	1.32 ± 0.39	1.29 ± 0.30	1.39 ± 0.36
P value	0.772		0.308		0.499		0.298

Nutrition intake data presented as mean ± SD.

The changes in quadriceps muscle area in the FAS are shown in Fig. 2A. In both groups, the area was slightly decreased at 2 weeks after surgery but recovered to exceed the value before the intervention by 9 weeks after discharge. In the test group, the area was significantly higher at 9 weeks after discharge than at 2 weeks after surgery (P <0.001), whereas there was no significant difference in the control group (P = 0.408). There was no significant difference between the two groups in the percentage change in quadriceps muscle area at 9 weeks after discharge from before the intervention. In addition, the percentage change from 2 weeks after surgery was higher on average in the test group, but there was no significant difference between the two groups (Table 4). An analysis was also performed in the PPS, and no significant difference was observed (data not shown). Changes in the hamstring area in the FAS are shown in Fig. 2B. Both groups showed near parallel changes, with a slight decrease at 2 weeks after surgery; however, by 9 weeks after discharge, the area had recovered to be close to the value before the intervention. The percentage change in the hamstring area at 9 weeks after discharge from before the intervention showed no significant difference between the two groups. Similarly, there was no significant difference between the two groups in the percentage change from 2 weeks after surgery (Table 4). No statistically significant difference was observed in the PPS (data not shown). The age of the test group was higher than that of the control group as a background factor; therefore, as a post hoc analysis, we performed an MMRM analysis using age and primary cancer as covariates. The percentage changes in the quadriceps area and hamstring area at 9 weeks after discharge showed no significant difference between the two groups before the intervention; similarly, the percentage change in the muscle areas showed no significant difference between the two groups from 2 weeks after surgery (Table 5).

Fig. 2.

 Changes in thigh skeletal muscle area: (A) quadriceps muscle area; (B) hamstring muscle area. For the quadriceps muscle in the test group, the area was significantly higher at 9 weeks after discharge than at 2 weeks after surgery (P <0.001). Values are plotted as mean ± SD.

Table 4.  Percentage change in thigh skeletal muscle area at 9 weeks after discharge.

Muscle area	From before the intervention			From 2 weeks after surgery
	Test group	Control group	P value	Test group	Control group	P value
Quadriceps	3.24 ± 6.63	2.34 ± 16.59	0.812	8.40 ± 7.57	4.44 ± 12.93	0.229
Hamstring	1.46 ± 13.12	1.71 ± 15.15	0.954	8.83 ± 10.97	8.81 ± 15.82	0.998

Percentage change (%) data are presented as mean ± SD.

Table 5.  Percentage change in thigh skeletal muscle area 9 weeks after discharge: MMRM analysis.

Muscle area	From before the intervention			From 2 weeks after surgery
	Test group	Control group	P value	Test group	Control group	P value
Quadriceps	3.18 ± 3.37	1.10 ± 3.15	0.615	3.57 ± 2.96	2.52 ± 2.82	0.750
Hamstring	3.12 ± 3.62	2.47 ± 3.39	0.892	−0.24 ± 3.39	4.40 ± 3.23	0.227

Adjusted for age and primary cancer. Percentage change (%) data are presented as mean ± SD.

The changes in isometric knee extension muscle strength are shown in Fig. 3A. Knee extension muscle strength was decreased in the test group at 2 weeks after surgery but recovered at 4 weeks after discharge, and no significant difference was observed between the two groups up to 9 weeks after discharge. Changes in isometric knee flexion muscle strength are shown in Fig. 3B. Knee flexion muscle strength was slightly decreased in both groups at 2 weeks after surgery but recovered to be higher than before the intervention at 4 weeks after discharge. No significant difference was observed between the two groups, including at 9 weeks after discharge. In addition, as a post hoc analysis, we performed an MMRM analysis using age and primary cancer as covariates, and no statistically significant difference was observed (data not shown).

Fig. 3.

 Changes in lower-limb muscle strength: (A) isometric knee extension muscle strength; (B) isometric knee flexion muscle strength. Values are plotted as mean ± SD.

The changes in 6MWD are shown in Fig. 4. Both groups showed a slight decline in the second postoperative week; however, at 4 weeks after discharge, the value recovered to be more than before the intervention. No significant difference was observed between the two groups. Post hoc analysis by MMRM also showed that there was no significant difference between the two groups (data not shown).

Fig. 4.

 Changes in 6MWD for test and control groups over the duration of the study. Values are plotted as mean ± SD.

Considering the impact of surgery in terms of FIM score trends, both groups showed a decline at 1 week after surgery, and by the time of discharge, the score had almost returned to pre-intervention levels at 2 weeks after surgery (Fig. 5). There was considerable inter-individual variability in the extent of the decline in the first post-operative week.

Fig. 5.

 Changes in FIM score for test and control groups over the duration of the study. Values are plotted as mean ± SD.

Adverse events were observed in four cases (16.7%) in the test group and three cases (12%) in the control group. In the test group, one patient developed wound infection and arrhythmia (Clavien-Dindo grade II), one patient developed respiratory failure (grade IIIa), one patient developed anastomotic leakage (grade IIIa), and one patient developed Roux-stasis syndrome (grade II). In the control group, one patient developed anorexia and dehydration (grade II), one patient developed Clostridium difficile enterocolitis (grade II), and one patient developed pancreatic fistula (grade II). However, all were considered to be postoperative complications or side effects of postoperative adjuvant chemotherapy and were not related to the study treatment.

DISCUSSION

This is the first prospective randomized controlled trial to examine the effects of perioperative rehabilitation and BCAA intake on postoperative muscle mass, strength, and walking ability in patients with gastrointestinal cancer. In both the group that received a carbohydrate supplement containing BCAAs immediately after rehabilitation and the group that received a carbohydrate supplement only, the quadriceps area remained almost unchanged at 2 weeks after surgery. In addition, the group that consumed BCAAs showed a significant increase at 9 weeks after discharge in comparison to 2 weeks after surgery, whereas no increase was observed in the group that consumed only carbohydrates. However, there was no difference between the two groups in the percentage change in the quadriceps area, which was the endpoint, at 9 weeks after discharge relative to before the intervention and 2 weeks after surgery. The hamstring area decreased slightly in both groups at 2 weeks after surgery but recovered to the same level as before the intervention by 9 weeks after discharge, and there were no significant difference between the two groups. Flexion and extension strength showed similar trends to muscle mass, decreasing slightly after surgery but recovering to the same level or a higher level as that before the intervention by 9 weeks after discharge. However, there was no difference between the two groups in terms of the measured values or rate of change. Furthermore, the 6MWD, an important indicator of motor function, decreased slightly after surgery in both groups but recovered quickly after discharge, and by 9 weeks after discharge, it had improved to a level exceeding that before the intervention. Based on these results, the usefulness of BCAAs in addition to carbohydrates as supplementary nutrition could not be demonstrated in recovering and improving muscle mass, muscle strength, and motor function. In this study, the intake of nutritional supplements containing amino acids occurred within 30 min immediately after exercise, which is considered to be useful for increasing muscle mass.¹⁴⁾ The supplement included essential amino acids with a high leucine content, which is considered to be useful for increasing muscle mass and strength.^17,18,19) Nevertheless, the following discussion considers some possible reasons for a lack effect.

At the time this study commenced, no studies examining the efficacy of protein-containing supplements after rehabilitation had been conducted on patients like those in this study (e.g., gastrointestinal cancer patients). Existing studies focused on patients who could not undergo the high-intensity exercise therapy used here, such as those with cerebrovascular disease or gait disorders. Therefore, we selected prior research using healthy middle-aged and elderly adult women as the control group,¹⁵⁾ because they were capable of performing the high-intensity exercise therapy typically administered after surgery for gastrointestinal cancer. However, in the previous study,¹⁵⁾ the background of subjects was very different from the special environment of postoperative gastrointestinal cancer. In particular, the condition of the postoperative gastrointestinal tract can lead to problems affecting rehabilitation and oral intake, such as postoperative pain and postoperative complications, in addition to a reduced bowel function. In fact, the PPS included 6 fewer patients in both groups relative to the FAS, with 18 and 19 patients in each group, respectively. The PPS was also defined as cases in which more than 70% of patients received endurance-enhancing exercise therapy, muscle-strengthening exercise therapy, or diet (jelly intake), and it is assumed that there was variation in implementation rates among the cases meeting this criterion in the FAS. It is also likely that the variation in dietary intake was influenced by the difference in postoperative dietary intake between patients with gastric and colorectal cancer. The possibility that the significantly older age of the protein-intake group may have had some influence cannot be excluded. Therefore, it is possible that the number of cases is insufficient to detect such differences.

Another consideration is the amount of BCAA intake relative to exercise intensity. It is possible that the BCAA intake was relatively insufficient relative to the amount of exercise. In a previous study²⁰⁾ demonstrating the efficacy of BCAA-rich supplements in patients with gait disturbance, the intervention group received the same supplement as in our study twice daily. Similarly, in a trial involving post-stroke patients,²¹⁾ the intervention group received a supplement containing nearly equivalent amounts of leucine. Despite these patients consuming equivalent or double the amount of BCAAs compared to our study, they underwent low-intensity exercise therapy because of disease-related limitations in activities such as walking. In contrast, in this study, in addition to endurance exercise (70% VO₂max), strength training exercises were also performed daily, and the muscle-building effects of this exercise were prominent; therefore, it is possible that the effects of BCAA-rich amino acid intake could not be detected. Furthermore, in previous RCTs that proved the usefulness of BCAA-rich amino acid intake, the control group did not take anything after exercise,^20,21) but in this study, to more accurately prove the usefulness of BCAA-enriched supplement intake after exercise, the control group took a carbohydrate supplement that did not contain any amino acids. Therefore, it is possible that the usefulness of protein intake could not be proven because of insufficient protein intake. A recent RCT²³⁾ targeting patients undergoing surgery for lumbar spinal canal stenosis showed that the group receiving the same BCAA-rich amino acid-containing carbohydrate supplement used in this study showed significantly increased lower-limb muscle strength at 12 weeks after surgery in comparison to the group taking a carbohydrate supplement that did not contain amino acids. In this previous study,²³⁾ supplements were taken twice daily, which was twice the amount of BCAA consumed in the present study. In fact, a meta-analysis report indicates that BCAA-enriched supplementation had a positive effect on lean body mass in adults and the elderly, and the timing of intake did not influence this effect.²⁴⁾ A previous meta-analysis report also indicated that the timing of intake did not influence this effect.²⁵⁾ The findings of these studies indicate the importance of increasing overall protein intake as opposed to altering the distribution throughout the day.²⁴⁾ This may be one reason why no differences were observed in the present study.

Trials on nutritional therapy for gastrointestinal cancers from the perioperative period to after discharge, such as this trial, have limitations. It is difficult to standardize the amount and content of regular diets other than the nutritional supplements. This may have an influence on the results. Therefore, most previous reports showing the usefulness of exercise therapy combined with nutritional therapy in the perioperative surgical period have used postoperative complications as the endpoint.^9,26,27,28) In the present study, the postoperative intervention with amino acid-containing supplement was only conducted for 1 week during hospitalization but lasted for 9 weeks after discharge, when it was extremely difficult to standardize dietary intake. To minimize this impact, we continued to provide detailed nutritional guidance during outpatient visits even after the patient was discharged from the hospital. As a result, no significant difference was observed in energy intake or protein intake between the two groups. Therefore, it is assumed that increasing the intake of BCAA-enriched nutritional supplement is necessary to determine its usefulness.

CONCLUSION

Perioperative exercise therapy combined with BCAA-enriched nutritional supplement intake did not significantly improve thigh skeletal muscle area, muscle strength, or walking ability after surgery in patients undergoing surgery for gastrointestinal cancer when compared with exercise combined with amino acid-free supplement intake. Future studies should consider increasing the intake of BCAA-enriched nutritional supplements to further clarify their effects, in addition to the selection of the target population and enrolment of an appropriate number of patients.