Effects of In-Hospital Physical Therapy on Activities of Daily Living in Patients with Hepatocellular Carcinoma

Activities of daily living (ADL) are frequently impaired in patients with hepatocellular carcinoma (HCC). In this retrospective study, we aimed to investigate the effects of physical therapy on ADLs in patients with HCC during hospitalization for cancer treatment. Nineteen patients with HCC were enrolled. During hospitalization, patients performed a combination of resistance training, stretching, and aerobic exercise (20–60 min/day). ADLs were assessed using the functional independence measure (FIM). Changes in FIM were evaluated by before–after analysis. No significant difference was seen in Child–Pugh class before and after physical therapy. The bilateral knee extension strength and chair stand test were significantly increased after physical therapy compared with before physical therapy (p = 0.001 and p = 0.008, respectively). The total FIM score was significantly increased after physical therapy compared with that before physical therapy (p = 0.0156). Among the 18 indexes of FIM, the stairs index was significantly improved after physical therapy compared with that before physical therapy (5.9 vs. 6.4 points, p = 0.0241). We demonstrated that physical therapy improved muscle strength without worsening liver function. Furthermore, physical therapy improved FIM, especially in the stairs index, in patients with HCC. Thus, physical therapy may be beneficial in patients with HCC during cancer treatment.


Introduction
Activities of daily living (ADLs) are frequently impaired in patients with cancer [1]. Impairment of ADLs is associated with a poor response to cancer treatment, mortality, and quality of life [1]. Patients underwent strength training for 10-20 min, targeting the bilateral quadriceps femoris muscles, gastrocnemius, and iliopsoas muscle. Bilateral quadriceps femoris muscle strength training was performed at 60% of the maximum voluntary contraction (MVC; moderate to high intensity) using a Combit CB-1 (Minato Medical Science Co., Ltd., Osaka, Japan) [20]. The quadriceps, gastrocnemius, and iliopsoas muscles were trained using the patient's weight. One set consisted of 10 repetitions, and a maximum of four sets were performed [15,19].

Stretching
Patients performed stretches for 3-5 min, targeting the quadriceps femoris muscles, the iliopsoas muscle, hip adductor muscles, and gastrocnemius muscles. Stretches were statically held for 20 s at the point of feeling tightness or slight discomfort [15,19].

Aerobic Exercise
Patients practiced voluntary walking with a goal of 10-30 min, depending on their motor skills. The intensity of exercise was adjusted to maintain a subjective rating of perceived exertion of 11-13 points on the Borg scale [15,19].

Diagnosis, Tumor Node Metastasis (TNM) Staging, and Treatment of HCC
HCC was diagnosed using a tumor biopsy or a combination of tests for serum tumor markers and imaging procedures, such as ultrasonography, computed tomography (CT), magnetic resonance imaging, and/or angiography. The clinical stage of HCC was evaluated by TNM staging based on the Liver Cancer Study Group of Japan criteria [21]. Treatment for HCC was selected based on the evidence-based clinical practice guidelines for HCC of The Japan Society of Hepatology [22].

Measurement of Psoas Muscle Index (PMI) and Skeletal Muscle Index (SMI)
PMI and SMI were evaluated using CT images obtained before and after physical therapy. The CT images were taken for the assessment of HCC in the outpatient department. A standard landmark for measuring the psoas muscle mass and skeletal muscle mass was the lower border of the third lumbar vertebra (L3). We measured the psoas muscle mass and skeletal muscle mass by manual tracings on CT images using Image-J software (National Institutes of Health, Bethesda, Maryland, USA, version Windows 10), and their sum was calculated [23]. Skeletal muscle mass and psoas muscle mass were normalized by the square of the height, and the data were expressed as PMI and SMI [24].

Maximum Muscle Strength Assessment of Knee Extension Strength
The maximum knee extension strength was measured during isometric contraction using Combit CB-1 according to the manufacturer's instructions. To prevent injury, several knee extension exercises were performed before the measurement. The measurement angle was set at 90 • of the knee joint flexion. The measurement posture was set to start with the trunk and both thighs secured with a belt while sitting on the seat of Combit CB-1, and the lower leg of the measurement side was secured to the attachment. During the measurement of maximum knee extension strength, a mechanical voice played from the Combit CB-1 asking the patient to apply force in the direction of knee extension. In addition, the measurer also asked the patient to put more force in the direction of knee extension. Each side of the knee extension strength was measured once. The measured value was displayed as the maximum knee extension strength on the Combit CB-1 monitor.

Grip Strength
An analog grip strength meter (Takei Machine Industry, Niigata, Japan) was used to measure grip strength. Left and right grip strength were measured in a standing position with the upper limbs hanging down to the side of the body. The test was completed twice each in both the left and right arms. A resting interval of at least 30 s was allowed between each measurement. The grip strength was defined as the average value of the higher grip strength of the left and right arms [25,26].

30-Second Chair-Stand Test (CS-30)
We employed the CS-30 to evaluate lower extremity muscle strength with a high retest reliability [27]. CS-30 was measured according to previous reports [28]. The patients were asked to sit on a chair that was 40 cm high. They were asked to position their legs shoulder width apart and to cross their arms in front of their chest as the starting posture. A single attempt was given before the measurement of CS-30. The test lasted 30 s. The subject was instructed to repeatedly stand and sit as many times as possible with their arms crossed.

Measurement of Walking Speed
Walking speed in meters per second (m/s) was measured by a 10-m walking test (10MWT). The 10MWT was modified from a previous report [29]. A stopwatch was used to measure the steady-state walking speed. To record the steady state walking speed during the 10MWT, 3 m acceleration and deceleration zones were added at the beginning and end of the course. Thus, the total walking distance was 16 m. The watch was started and stopped when the patient's toe passed over the lines marking the start and end of the 10-m course, respectively [26]. We conducted the 10MWT twice, and the average walking speed was used for the analysis. Two subjects used walking aids.

Measurement of FIM
FIM is an assessment tool comprising 18 items, including eating, grooming, bathing, dressing the upper body, dressing the lower body, toileting, bladder management, bowel management, bed/chair/wheelchair, toilet, tub/shower, walk/wheelchair, stairs, comprehension, expression, social interaction, problem solving, and memory. Thirteen items belong to the motor subscale, and five items belong to the cognitive subscale, including comprehension, expression, social interaction, problem solving, and memory [7]. All of the items were scored as follows: 1 (total assist), 2 (maximal assist), 3 (moderate assist), 4 (minimal assist), 5 (supervision), 6 (modified independence), and 7 (complete independence). The FIM item scores were added together for a total score ranging between 18 and 126, or a total motor score ranging between 13 and 91 and a total cognitive score ranging between 5 and 35 [30]. These assessments were evaluated by physical therapists qualified in cancer rehabilitation with more than 13 years of experience.

Statistical Analysis
Data are expressed as median (interquartile range (IQR)), range, or number. Changes in variables between before and after physical therapy were evaluated using Wilcoxon signed-rank tests. The level of statistical significance was set at p < 0.05. These analyses were performed using JMP Pro ® 14 (SAS Institute Inc., Cary, NC, USA).

Patient Characteristics
The patient characteristics are summarized in Table 2. The median age of the patients was 78 years, and 31.6% were women. The median BMI was 21.2 kg/m 2 . All of the patients had a performance status of grade 0 or 1, and the median FIM score was 126 points.    More than 80% of patients had stage II HCC. The median Child-Pugh score was 5, and 78.9% of patients were Child-Pugh class A. The prevalence of sarcopenia was 31.6%. The median hospitalization time was 10 days, and the median duration of exercise therapy was 5 days. The median right knee extension strength and left knee extension strength were 25.2 kgf and 24.2 kgf, respectively. The implementation rate was 66.7% for resistance training, stretching, standing stepping, calf raise, and half squat. The implementation rate for aerobic exercise was 75% (Table 2).

Changes in Liver and Renal Function after Physical Therapy
No significant differences were observed in the serum levels of AST, ALT, LD, ALP, and GGT (Table 3). There was no significant difference in the Child-Pugh score and Child-Pugh class before and after physical therapy (Table 3). No significant difference was seen in eGFR (Table 3). Table 3. Changes in liver and renal functions after physical therapy.

Changes in Skeletal Muscle Mass after Physical Therapy
There was no significant decrease in PMI or SMI after physical therapy compared with before physical therapy ( Figure 1A,B).

Changes in Walking Speed and Muscle Strength after Physical Therapy
No significant difference was seen in walking speed before and after physical therapy ( Figure  2A). There was no significant difference in grip strength before and after physical therapy ( Figure  2B). There was a significant increase in right and left knee extension strength after physical therapy compared with before physical therapy ( Figure 2C,D). CS-30 was significantly improved after physical therapy compared with that before physical therapy ( Figure 2E).

Changes in Walking Speed and Muscle Strength after Physical Therapy
No significant difference was seen in walking speed before and after physical therapy (Figure 2A). There was no significant difference in grip strength before and after physical therapy ( Figure 2B). There was a significant increase in right and left knee extension strength after physical therapy compared with before physical therapy ( Figure 2C,D). CS-30 was significantly improved after physical therapy compared with that before physical therapy ( Figure 2E).

Changes in Walking Speed and Muscle Strength after Physical Therapy
No significant difference was seen in walking speed before and after physical therapy ( Figure  2A). There was no significant difference in grip strength before and after physical therapy ( Figure  2B). There was a significant increase in right and left knee extension strength after physical therapy compared with before physical therapy ( Figure 2C,D). CS-30 was significantly improved after physical therapy compared with that before physical therapy ( Figure 2E).

Changes in FIM Score and All Items of FIM after Physical Therapy
The total FIM score was significantly increased after physical therapy compared with before physical therapy (Figure 3). The stairs index is a motor index of FIM, and was the only item that was

Changes in FIM Score and All Items of FIM after Physical Therapy
The total FIM score was significantly increased after physical therapy compared with before physical therapy (Figure 3). The stairs index is a motor index of FIM, and was the only item that was significantly improved after physical therapy (Figure 4). There were no significant changes in the scores of the other motor and cognitive indexes between before and after physical therapy (Figure 4). significantly improved after physical therapy (Figure 4). There were no significant changes in the scores of the other motor and cognitive indexes between before and after physical therapy (Figure 4).

Discussion
We demonstrated the safety and beneficial effects of in-hospital physical therapy, including resistance exercise, for patients with HCC. Liver and renal function did not worsen after physical therapy. Physical therapy with personalized intensity improved muscle strength with no reduction in muscle mass during hospitalization for HCC treatment. In addition, physical therapy improved FIM, especially in the stairs index, in patients with HCC during hospitalization for cancer treatment.

Discussion
We demonstrated the safety and beneficial effects of in-hospital physical therapy, including resistance exercise, for patients with HCC. Liver and renal function did not worsen after physical therapy. Physical therapy with personalized intensity improved muscle strength with no reduction in muscle mass during hospitalization for HCC treatment. In addition, physical therapy improved FIM, especially in the stairs index, in patients with HCC during hospitalization for cancer treatment.
In our study, liver and renal function were not worsened by physical therapy. On the other hand, García-Pagàn et al. reported that moderate exercise increased the risk of variceal bleeding in patients with esophageal varices [31]. Saló et al. reported that moderate physical exercise may cause marked impairment in renal function in patients with liver cirrhosis [32]. Although it remains unclear why the liver function did not worsen with physical therapy, a possible reason is a difference in the type of exercises used in our study compared with that of previous studies. In our study, we mainly employed resistance training. However, previous studies employed aerobic exercise such as cycloergometric exercise [31,32]. The intensity of aerobic exercise is generally higher than that of resistance exercise [33], and cardiopulmonary function is known to be impaired in patients with HCC [34]. Therefore, aerobic exercise is a cardiopulmonary burden in patients with HCC. Our results may indicate that resistance exercise is more suitable than aerobic exercise for patients with HCC.
In this study, our physical therapy program was able to maintain muscle mass in patients with HCC. Our results were in good agreement with a previous report of HCC patients [14]. In addition, we demonstrated that our physical therapy program improved the muscle strength of the lower limbs. Although the reason the physical therapy program improved the muscle strength of the lower limbs remains unclear, it may be because resistance exercises were performed at a personalized intensity using a machine such as COMBIT CB-1. COMBIT CB-1 is able to precisely assess the maximal muscle strength of the lower limbs and allows the operator to set the appropriate intensity of exercise [20], which may result in increased muscle strength in the lower limbs. In fact, Nadia Schott et al. reported that exercise using machine training significantly increased the muscle strength of the lower limbs [35].
We first demonstrated that physical therapy increased the FIM score in patients with HCC. In previous studies, physical therapy has been reported to increase the FIM score in patients with various cancers, including colorectal cancer [10] and pancreatic cancer [36]. Thus, our results are in good agreement with these previous reports. Saotome et al. reported that an increase in FIM score by cancer rehabilitation was associated with prolonged survival in patients with cancer [37]. Moreover, an increase in FIM score through physical therapy has been reported to improve cognitive function in patients with cancer [13,38]. Furthermore, an increase in FIM score has been reported to be associated with an improved quality of life in patients with cancer. Therefore, evaluation of FIM seems to be important for the management of patients with HCC.
In this study, our physical therapy program increased the FIM score in patients with HCC. A possible reason for an increase in the FIM score is that we performed machine training with appropriate exercise intensity using COMBIT CB-1. Furthermore, a feature of our physical therapy program was that we mainly focused on exercising the lower-limb muscles, which is associated with physical performance [39]. As a result, physical therapy improved CS-30, an index for the strength of lower limb muscles in this study. In fact, among all 18 factors consisting of the FIM score, the ability to climb stairs was the only factor that was improved by physical therapy in this study. Matsufuji et al. also reported that chair stand exercises improved ADLs in patients on hemodialysis aged >60 years in a randomized controlled trial [40]. Yoshimura et al. also reported that an in-hospital chair-stand exercise was independently associated with an improvement in FIM-motor scores [41]. These findings indicate that physical therapy improved lower limb strength and subsequently the ability to climb stairs, leading to an increase in FIM score in this study.
This study has several limitations. First, this was a single-center study with a small sample size. Second, this was a retrospective chart review with no control group, which cannot prove the efficacy of physical therapy. Third, ADLs were assessed using only the FIM score and not by other methods such as the cancer functional assessment set [42]. Fourth, we could not perform a multivariate analysis because of the small sample size, and it remains unclear what type of physical therapy was associated with an improvement of FIM. Thus, the usefulness of physical therapy should be evaluated by a multi-center prospective study with a large sample size by using multiple assessments for ADLs. Fifth, Saotome et al. have reported that survival was significantly improved in patients with a total FIM score ≥80 after cancer rehabilitation [37]. In our study, all patients showed a total FIM score ≥ 80, even at the admission of the hospital. Therefore, it remains unclear if physical therapy had an impact on prognosis in our study. It also remains unclear which subscale of the FIM is important for survival. Thus, further studies should be focused on an association between an increase in FIM scores/the subscale of the FIM and an improvement in survival.

Conclusions
In this study, we performed in-hospital physical therapy, including resistance exercises, at a personalized intensity for patients with HCC. We demonstrated that in-hospital physical therapy did not worsen hepatic function. We also showed that exercise improved muscle strength with no reduction in muscle mass. Furthermore, we also showed that exercise improved the stair index of FIM in patients with HCC. Thus, in-hospital physical therapy may improve the ability to climb stairs in patients with HCC. Future research is needed to more clearly assess the benefits of physical therapy for ADL performance.