Resistance and aerobic exercise intervention during chemotherapy in patients with metastatic cancer: a pilot study in South Korea
Introduction
Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass leading to progressive functional impairment (1). Loss of skeletal muscle mass, called sarcopenia, is a major component of cancer cachexia and occurs frequently in patients with metastatic cancer (2). The multiple computed tomography (CT) images obtained during cancer treatment provide an opportunity to objectively quantify muscle loss at various time points. The presence of sarcopenia at baseline is associated with negative clinical effects, including deterioration in quality of life (QoL), increased risk of treatment-related toxicities, and reduced survival in patients with metastatic cancer (3-5). Recent studies also showed that a higher amount of muscle loss during palliative chemotherapy is associated with shorter survival (6,7).
The management of sarcopenia has emerged as a key issue in cancer patients. Resistance and aerobic exercises have been shown to increase muscle strength and function and represent an attractive treatment strategy for cancer-related sarcopenia (8,9). It has been reported that building or maintaining muscle mass through exercise training is a safe and effective adjunct therapy in patients with metastatic cancer (10). However, in day-to-day clinical practice, cancer patients commonly report unmet needs with respect to information about exercise methods and access to exercise programs (11). A lot of healthcare professionals treating cancer patients have no experience with exercise regimens and fail to give specific advice to their patients. Furthermore, it is difficult to draw conclusions about the optimal duration, frequency, or intensity of exercise because the types of exercise interventions used in previous studies involving patients with metastatic cancer were heterogeneous.
To date, no prospective studies have been designed to determine the feasibility of an exercise programs for patients with metastatic cancer in South Korea. The purpose of this pilot study was to provide initial experimental data on the feasibility and safety of an exercise intervention for patients with metastatic cancer during palliative chemotherapy. We present the following article in accordance with the STROBE reporting checklist (available at https://dx.doi.org/10.21037/apm-21-1432).
Methods
Participants
Participants were eligible if they had a plan to receive first-line chemotherapy for metastatic solid cancer, were aged ≥20 years, had an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and a life expectancy ≥4 months. Exclusion criteria were as follows: brain metastases; bone metastases with a high risk of fracture; musculoskeletal disorders that inhibit participants from exercise; symptomatic heart disease including congestive heart failure, arrhythmia, or myocardial infarction diagnosed within the last six months; and uncontrolled hypertension. The risk of pathologic fracture in patients with bone metastases was determined using Mirels’ classification, which was assessed by a radiologist (12). The study was conducted in compliance with the Declaration of Helsinki (as revised in 2013) and was approved by the Institutional Review Board of Gil Medical Center (No. GBIRB2017-224). All participants provided written informed consent. This study is registered at the Clinical Research Information Service (No. KCT0003147).
Exercise intervention
The exercise intervention involved supervised and home-based exercise over 12 weeks. Supervised exercise took place in small groups of one to four participants under the supervision of an accredited physical therapist (J-H.K) twice a week in the hospital exercise room. Each session lasted approximately 60 minutes, consisting of stretching, aerobic, and resistance exercises. Aerobic exercise was performed using cycle ergometry. Its intensity was equivalent to 60–85% of each patient’s maximum heart rate and that lasted 20 minutes in the first week and 30 minutes in weeks 2–12. The age-predicted maximum heart rate was calculated by subtracting age from 220. Resistance exercise included nine types of bodyweight exercises. Resistance exercises are strength training exercises that use an individual's own weight to provide resistance against gravity. Participants were instructed to perform nine types of exercises (bridge, crunch, seated butterfly, push-up, squat, standing leg curl, shoulder press, kneeling leg extension, and bird-dog) with three sets of 10 repetitions for each exercise; for standing leg curl and bird-dog, one set was to hold the position for more than 10 seconds and repeat on the other side. The home-based exercise consisted of walking and nine resistance exercises described above and was performed three times a week. The intensity of exercise was adapted to the physical condition of the participant.
Outcome measurements
Primary outcome measures were safety and feasibility of the exercise intervention. Safety was assessed by recording the incidence and severity of any adverse events throughout the exercise intervention. Any adverse event occurring during a supervised exercise session was recorded by the physical therapist. Feasibility was assessed as the percentage of patients who did not complete the 12-week exercise program (participant attrition rate) and the rate of attended exercise sessions out of the planned sessions (attendance rate). Participants wrote home-based exercise diaries that recorded the date of exercise, the number of sets performed per exercise, and adverse effects during the exercise and submitted them every week. They were also asked reasons for the non-attendance and delay of the exercise session.
Secondary outcome measures were skeletal muscle mass and strength, functional capacity, QoL, and fatigue. Secondary outcomes were assessed at baseline and post-intervention. Quantitative assessments of skeletal muscle mass were performed using CT and bioelectrical impedance analysis (BIA). We quantified skeletal muscle mass (cm2) in a single cross-sectional area at the first (L1) or third lumbar (L3) level of the lumbar spine. Skeletal muscle area was quantified using in-house software (Gachon_DeepBody developed in the Gil Medical Center, Incheon, Korea) that automatically identified skeletal muscle and calculated the muscle area on CT images (Hounsfield units: from −29 to 150 for skeletal muscle). Sarcopenia was defined as an L3 muscle index (L3 muscle area/height2) of ≤55 cm2/m2 for men and ≤39 cm2/m2 for women (L1 muscle index cutoffs: 46 cm2/m2 for men and 29 cm2/m2 for women) (13). Appendicular skeletal muscle mass (ASM) was assessed using direct segmental 8-point multifrequency BIA (InBody770, InBody Co., Ltd, Seoul, Korea). ASM was defined as the sum of the muscle mass in both the arms and legs.
Handgrip strength was assessed in the nondominant hand using a Jamar Plus+ Digital Hand Dynamometer (Patterson Medical, Warrenville, IL, USA). The patients performed the test while sitting comfortably with shoulder adducted and forearm neutrally rotated, elbow flexed to 90°, and forearm and wrist in a neutral position. For each assessment of handgrip strength, three measurements were made, and the highest score was used.
Functional capacity was measured using a 6-meter walk test (14). The testing distance included 2-meter acceleration and deceleration zones, with the inner 6-meter zone being the distance over which gait was timed. Gait speeds were calculated by dividing 6 meters by the time taken (meters/second).
QoL and fatigue evaluation was performed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) (15), Functional Assessment Cancer Therapy-General (FACT-G) (16), and Functional Assessment of Chronic Illness Therapy-Fatigue Questionnaire (FACIT-Fatigue) (17). The minimally important differences (MIDs) for interpreting the degree of change within a group were defined as follows: 10 for EORTC QLQ-C30 (18); 9 for total FACT-G (19); 10 for FACIT-Fatigue (20).
Statistical analysis
Descriptive statistics were reported as proportions or means ± standard deviations (SDs). Differences between pre-and post-intervention values of continuous variables were analyzed using the paired t-test or Wilcoxon signed-rank test. Two-sided P values <0.05 were considered statistically significant. The analysis was performed using IBM SPSS Statistics for Windows, Version 25.0 (IBM Corp., Armonk, NY, USA).
Results
Between September 2017 and February 2018, 19 patients were enrolled in this pilot study. The baseline characteristics of the study population are presented in Table 1. The median age was 60 years, and 10 patients (52.6%) were men. All patients had metastatic cancer. The primary tumors were as follows: lung cancer (n=9), gynecologic cancer (n=5), soft tissue sarcoma (n=3), gastric cancer (n=1), and mesothelioma (n=1). The ECOG performance status was 1 in 12 (63.2%) patients. Sarcopenia was present in 13 patients (68.4%).
Table 1
| Variable | n (%) |
|---|---|
| Age (years) | |
| Median [range] | 60 [30–74] |
| Male | 10 (52.6) |
| BMI (kg/m2) | |
| Underweight (<18.5) | 0 (0.0) |
| Normal (≥18.5, <23.0) | 8 (42.1) |
| Overweight (≥23.0, <25.0) | 7 (36.8) |
| Obese (≥25.0) | 4 (21.0) |
| Stage (TNM) | |
| IV | 19 (100.0) |
| Performance status (ECOG) | |
| 0 | 7 (36.8) |
| 1 | 12 (63.2) |
| 2 | 0 (0.0) |
| Cancer type | |
| Non-small cell lung cancer | 8 (42.1) |
| Small cell lung cancer | 1 (5.3) |
| Soft tissue sarcoma | 3 (15.8) |
| Cervical cancer | 3 (15.8) |
| Endometrial cancer | 2 (10.5) |
| Gastric cancer | 1 (5.3) |
| Malignant pleural mesothelioma | 1 (5.3) |
| First-line regimen | |
| Pemetrexed-cisplatin | 8 (42.1) |
| Paclitaxel-platinum | 3 (15.8) |
| Doxorubicin-cisplatin | 2 (10.5) |
| Bevacizumab-paclitaxel-cisplatin | 1 (5.3) |
| Etoposide-cisplatin | 1 (5.3) |
| Capecitabine-oxaliplatin | 1 (5.3) |
| Doxorubicin-ifosfamide | 1 (5.3) |
| Gemcitabine-docetaxel | 1 (5.3) |
| Pembrolizumab | 1 (5.3) |
| Bone metastasis# | 1 (5.3) |
| Sarcopenia | 13 (68.4) |
#, the patient had pelvic bone metastases. BMI, body mass index; ECOG, Eastern Cooperative Oncology Group.
Five patients withdrew consent before the exercise intervention. Reasons for withdrawal include fear of exacerbating cancer-related symptoms (n=2), transportation issues (n=2), and unknown (n=1). The participant attrition rate of the 12-week exercise program was 28.6% (4/14). Four patients discontinued the exercise program due to disease progression (n=2, aggravation of cancer pain; n=1, deterioration in performance status) and chemotherapy-induced toxicity (n=1). The mean attendance rate of the supervised exercise sessions was 64.9% (range, 16.7–95.8%). An attendance rate of 75% or higher was achieved in eight patients (57.1%). The main reasons for non-attendance were personal reasons (27.6%), public holidays (19.7%), fatigue (13.2%), and hospitalization (10.5%). No adverse events or skeletal complications occurred during the supervised exercise sessions. Home-based exercise was performed at an average rate of 67.1% (24.1 sessions of planned 36 sessions).
Baseline and post-intervention values for skeletal muscle mass, gait speed, and hand grip strength are reported in Table 2. Among participants in the exercise program, there were no significant changes in the L3 muscle area (mean change, −0.7 cm2, P=0.869) and ASM (mean change, 0.1 kg, P=0.661). The gait speed improved after the exercise intervention (mean change, 0.11 m/s) but the improvement was not statistically significant (P=0.120). The grip strength showed no significant change (mean change, −2.7 kg, P=0.075).
Table 2
| Measures | Baseline, mean (SD) | Post-exercise, mean (SD) | Change, mean (95% CI) | P value* |
|---|---|---|---|---|
| L1/L3 muscle area (cm2) | 109.4 (16.2) | 108.7 (16.5) | −0.7 (−10.2 to 8.7) | 0.869 |
| Appendicular skeletal muscle mass (kg) | 18.1 (4.8) | 18.2 (4.2) | 0.1 (−0.5 to 0.8) | 0.661 |
| 6-meter walk (m/s) | 1.18 (0.24) | 1.29 (0.16) | 0.11 (−0.03 to 0.26) | 0.120 |
| Hand grip strength (kg) | 27.5 (10.9) | 24.8 (10.5) | −2.7 (−5.8 to 0.3) | 0.075 |
*, paired
Table 3 shows changes in patient-reported outcomes. Significant improvements were detected in the total score (P=0.037) and emotional well-being domain (P=0.006) of the FACT-G after the exercise intervention. There were also significant improvements in physical, social, and cognitive function on the EORTC QLQ-C30. However, there was no improvement in the symptom scales of the EORTC QLQ-C30 or FACIT-Fatigue scale.
Table 3
| Measures | Baseline, mean (SD) | Post-exercise, mean (SD) | Change, mean (95% CI) | MID, improvement | P value |
|---|---|---|---|---|---|
| FACT-G | |||||
| Total score | 67.3 (18.5) | 76.6 (11.3) | 9.3 (0.7 to 17.9) | 9 | 0.037 |
| Physical well-being | 20.5 (6.3) | 23.3 (4.4) | 2.8 (−1.0 to 6.6) | 3 | 0.128 |
| Social/family well-being | 17.1 (5.7) | 16.8 (3.7) | −0.3 (−2.8 to 2.2) | 2 | 0.796 |
| Emotional well-being | 15.0 (6.0) | 20.3 (2.7) | 5.3 (1.8 to 8.7) | 2 | 0.006 |
| Functional well-being | 14.7 (5.7) | 16.9 (4.9) | 2.3 (−1.0 to 5.5) | 3 | 0.157 |
| EORTC QLQ-C30 | |||||
| Global health status | 52.7 (31.6) | 62.5 (19.9) | 9.7 (−7.1 to 26.6) | 10 | 0.231 |
| Functional scales | |||||
| Physical function | 76.1 (20.3) | 85.6 (8.9) | 9.4 (−4.2 to 23.1) | 10 | 0.035* |
| Role function | 88.8 (14.7) | 91.6 (13.3) | 2.8 (−4.8 to 10.4) | 10 | 0.414* |
| Emotional function | 75.0 (21.3) | 87.5 (13.1) | 12.5 (−0.2 to 25.2) | 10 | 0.053 |
| Cognitive function | 80.5 (24.4) | 94.4 (10.9) | 13.9 (2.1 to 25.7) | 10 | 0.025 |
| Social function | 66.7 (29.3) | 80.6 (21.1) | 13.9 (5.0 to 22.7) | 10 | 0.017* |
| Symptom scales | |||||
| Fatigue | 36.1 (23.7) | 25.0 (6.9) | −11.1 (−25.5 to 3.3) | −10 | 0.118 |
| Nausea & vomiting | 15.3 (27.0) | 16.7 (20.1) | 1.4 (−18.5 to 21.3) | −10 | 0.881 |
| Pain | 29.2 (25.7) | 19.4 (17.2) | −9.7 (−26.1 to 6.8) | −10 | 0.223 |
| Dyspnea | 25.0 (28.9) | 13.9 (17.2) | −11.1 (−27.6 to 5.4) | −10 | 0.083* |
| Insomnia | 30.5 (36.1) | 27.8 (23.9) | −2.8 (−23.9 to 18.3) | −10 | 0.679* |
| Appetite loss | 36.1 (33.2) | 22.2 (32.8) | −13.9 (−38.6 to 10.8) | −10 | 0.241 |
| Constipation | 22.2 (29.6) | 22.2 (25.9) | 0.0 (−23.9 to 23.9) | −10 | 0.595* |
| Diarrhea | 16.6 (26.5) | 0.0 (0.0) | −16.7 (−33.6 to 0.2) | −10 | 0.063* |
| Financial difficulties | 19.4 (33.2) | 11.1 (21.7) | −8.3 (−24.3 to 7.6) | −10 | 0.257* |
| FACIT-Fatigue scale | 35.5 (9.4) | 40.7 (7.6) | 5.2 (−0.2 to 10.5) | 10 | 0.058 |
*, Wilcoxon signed-rank test. SD, standard deviation; CI, confidence interval; MID, Minimal important difference; FACT-G, Functional Assessment of Cancer Therapy-General; EORTC QLQ-C30, The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FACIT, Functional Assessment of Chronic Illness Therapy.
Discussion
The current study is one of the first to evaluate the feasibility and safety of exercise intervention for Korean patients with metastatic cancer who underwent palliative chemotherapy. There is growing evidence that exercise interventions are safe and feasible in patients with metastatic cancer and even in the presence of bone metastases (10,21). A review article reported that intervention attrition rates ranged from 6% to 58% (mean 25%) and exercise session attendance ranged from 59% to 100% (10). The participant attrition rate and attendance rate of this study are similar to those of the previous studies. Therefore, our study showed that supervised combined aerobic and resistance exercise is feasible and safe during palliative chemotherapy.
Recent systematic reviews and meta-analyses showed that exercise interventions for patients with metastatic cancer are associated with improvement in QoL and physical function; supervised exercise interventions seem to confer more benefit than non-supervised interventions (22,23). In our study, total score and emotional well-being of FACT-G improved significantly on the average more than MID. Emotional functioning of the EORTC QLQ-C30 subscales slightly increased, although not significant. Physical exercise might therefore be a suitable approach for improving QoL and reducing emotional distress in patients with metastatic cancer.
Fatigue is one of the most prevalent symptoms reported by patients with cancer during the course of their disease and its treatment (24). Cancer therapies, especially chemotherapy, can result in cancer-related fatigue (CRF) and exacerbate existing CRF (25). Several studies have investigated the effect of exercise on CRF as either the primary or secondary outcome, and systemic reviews and meta-analyses have documented significant improvements in CRF following exercise interventions (26). However, previous clinical studies evaluating the efficacy of exercise against CRF have mainly been conducted in patients with non-metastatic cancer or cancer survivors. The improvement of CRF in metastatic settings remains unclear. Recent systematic reviews and meta-analyses of metastatic cancer patients did not find a significant improvement in CRF (22,23). We evaluated CRF using the FACIT-Fatigue scale and EORTC QLQ-C30 fatigue subscale; there was no significant reduction in fatigue after the exercise intervention. In contrast to the curative setting, patients with metastatic cancer have an ongoing tumor burden and are influenced by ongoing chemotherapy, which might make it difficult to improve CRF. Therefore, in metastatic settings, avoiding exacerbation of CRF may be a realistic goal (22).
Muscle wasting is highly prevalent in patients with advanced cancer and is associated with an increased risk of chemotherapy-related toxicity, worse QoL, and poor prognosis (4,5,27). Furthermore, administration of chemotherapy has been shown to promote depletion of skeletal muscle mass (28,29); skeletal muscle loss is more frequent in patients receiving cytotoxic chemotherapy than in patients receiving molecular targeted therapy (30). Preservation of muscle mass is presented as a novel strategy to counteract chemotherapy toxicity and improve QoL in cancer patients (29). Recently, clinical studies are underway to evaluate the effect of various pharmacologic agents as well as resistance exercise on muscle mass. Based on this background, it is clinically important to accurately measure muscle mass and monitor muscle mass changes during cancer treatment. Our study evaluated changes in skeletal muscle mass using two modalities: CT scans used for tumor evaluation and BIA. In our study, there was no significant reduction in muscle mass after exercise interventions in patients receiving palliative chemotherapy.
The importance of exercise therapy in cancer patients has been suggested in many studies, but exercise therapy has not been widely implemented in a real-world setting. A number of barriers affect the implementation of exercise interventions in patients with metastatic cancer (31). Patient-related factors include lack of awareness of the safety and benefits of exercise. In this study, patient concern was one of the main reasons for withdrawing consent before the exercise intervention. Given that patients with cancer have various cancer-related symptoms and decreased physical capabilities, exercise interventions need to be individually tailored. The implementation of an exercise program requires adequate equipment and facilities, as well as physical therapy specialists. Financial support for insurance systems, in addition to research funding, is needed for medical institutions to provide exercise programs for cancer patients.
Several limitations of our pilot study warrant consideration. The small number of participants limits statistical power to detect a significant difference. Another limitation of the study was the absence of a control group. The effectiveness of exercise on secondary outcomes could not be confirmed by comparing between patients who participated in the exercise program and those who did not. The benefits of exercise intervention in cancer patients can be defined following a randomized controlled trial with a large population. Third, thresholds for feasibility were not defined prior to the start of the study. Feasibility was determined by referring to previous studies conducted to evaluate feasibility and/or tolerance of the exercise intervention. Fourth, we did not apply an accurate figure system for indicating the intensity of the exercise like 1-RM in building our exercise program. Furthermore, adaptation of the exercise intensity was carried out, not in accordance with systemic protocol, but based on the subjective decision of physical therapist. This could be a factor that limits designing systemic exercise program. However, since each patients’ strength and endurance varies, it seems rational to flexibly adopt the exercise intensity depending on the circumstance of each session. Finally, the minor adverse events were underestimated since the safety profile was not systematically recorded according to established criteria such as Common Terminology Criteria for Adverse Events (CTCAE). However, there was no serious symptom that required the termination of the exercise.
In conclusion, our results show that exercise interventions are feasible and safe in patients with metastatic solid cancer. Exercise interventions can improve QoL and prevent skeletal muscle loss and fatigue deterioration during palliative chemotherapy. Further randomized controlled studies are warranted to confirm these findings.
Acknowledgments
Funding: This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (Grant No. HA17C0045). The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://dx.doi.org/10.21037/apm-21-1432
Data Sharing Statement: Available at https://dx.doi.org/10.21037/apm-21-1432
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/apm-21-1432) and report that this study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (Grant No. HA17C0045). The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in compliance with the Declaration of Helsinki (as revised in 2013) and was approved by the Institutional Review Board of Gil Medical Center (No. GBIRB2017-224). All participants provided written informed consent.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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